Pyrrolopyridazine compounds

ABSTRACT

A pyrrolopyridazine compound having the formula (I) or a pharmaceutically acceptable salt thereof:  
                 
 
     wherein, R 1  is a C 2 -C 6  alkenyl group, a halogeno C 2 -C 6  alkenyl group, a C 3 -C 7  cycloalkyl group which may be optionally substituted or a C 3 -C 7  cycloalkyl- C 1 -C 6  alkyl group which may be optionally substituted. R 2  is a C 1 -C 6  alkyl group. R 3  is a hydroxymethyl group, a C 2 -C 6  aliphatic acyloxymethyl group, a C 6 -C 10  arylcarbonyloxymethyl group which may be optionally substituted, a C 1 -C 6  alkoxycarbonyloxymethyl group, a formyl group, a carboxyl group, a C 1 -C 6  alkoxycarbonyl group or a C 6 -C 10  aryloxycarbonyl group which may be optionally substituted. R 4  is a C 6 -C 10  aryl group which may be optionally substituted. A is an imino group, an oxygen atom or a sulfur atom. These compounds exhibit excellent gastric acid secretory inhibition activity and gastric mucous membrane protection activity etc. They are useful for prevention or treatment of ulcerative diseases and for  Helicobacter pylori  infections.

[0001] This is a continuation application of international application PCT/JP01/00820 filed Feb. 6, 2001.

TECHNICAL FIELD

[0002] This invention relates to pyrrolopyridazine derivatives or pharmaceutically acceptable salts thereof; to pharmaceutical compositions comprising a pyrrolopyridazine derivative or a pharmaceutically acceptable salt thereof (preferably compositions for the prevention or treatment of ulcerative disease) as an active ingredient; to the use of a pyrrolopyridazine derivative or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition (preferably a composition for the prevention or treatment of ulcerative disease); or to a method for the prevention or treatment of disease (preferably ulcerative disease), which method comprises administering a pharmaceutically effective amount of a pyrrolopyridazine derivative or a pharmaceutically acceptable salt thereof to a warm-blooded animal (preferably a human).

BACKGROUND OF THE INVENTION

[0003] It has been considered that an inbalance between aggressive factors and protective factors against the gastric mucous membrane induces peptic ulcers. Gastric acid secretion is an aggressive factor and suppression of gastric acid secretion is useful in the prevention and treatment of the disease. Anticholinergic agents, histamine H₂ receptor antagonists such as cimetidine and the like and proton pump inhibitors such as omeprazole and the like have been clinically used as a gastric acid secretion inhibitor. Although these agents are excellent therapeutic agents for ulcerative disease, the disease may recur after cessation of the therapy. It has been recently reported that Helicobacter pylon relates to recurrence of the ulcerative disease. Actually there have been some attempts to use a gastric acid secretion inhibitor in combination with an antibacterial agent for treatment of the disease.

[0004] Accordingly a compound that exhibits potent gastric acid secretory inhibition activity, excellent gastric mucous membrane protection activity and potent antibacterial activity against Helicobacter pylori would be expected to be an excellent medicament (preferably a prophylactic and therapeutic agent for ulcerative disease).

[0005] Some pyrrolopyridazine derivatives that have gastric acid secretory inhibition activity and gastric mucous membrane protection activity have been known (for example, WO 91/17164, WO 92/06979, WO 93/08190 and the like). The activity against Helicobacter pylori of some pyrrolopyridazine derivatives has also been known (for example, Japanese Patent Application Publication Hei 7-247285 and the like).

DISCLOSURE OF THE INVENTION

[0006] The inventors have continued an investigation on the pharmacological activities of pyrrolopyridazine derivatives in order to discover a medicament (preferably an agent for ulcerative disease) that exhibits potent gastric acid secretory inhibition activity, protects gastric mucous membranes and has excellent antibacterial activity against Helicobacter pylori for a long time. As a result, they found that some pyrrolopyridazine derivatives substituted with specific substituents at the 3-position exhibit potent gastric acid secretory inhibition activity and gastric mucous membrane protection activity and exhibit excellent antibacterial activity against Helicobacter pylori.

[0007] The pyrrolopyridazine derivative, i.e., compound, of the present invention has the following formula:

[0008] wherein:

[0009] R¹ represents a C₂-C₆ alkenyl group, a halogeno C₂-C₆ alkenyl group, a C₃-C₇ cycloalkyl group which may be optionally substituted with C₁-C₆ alkyl or a C₃-C₇ cycloalkyl-C₁-C₆ alkyl group which may be optionally substituted with C₁-C₆ alkyl; R² represents a C₁-C₆ alkyl group;

[0010] R³ represents a hydroxymethyl group, a C₂-C₆ aliphatic acyloxymethyl group, a C₆-C₁₀ arylcarbonyloxymethyl group which may be optionally substituted with substituents selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy and halogeno, a C₁-C₆ alkoxycarbonyloxymethyl group, a formyl group, a carboxyl group, a C₁-C₆ alkoxycarbonyl group or a C₆-C₁₀ aryloxycarbonyl group which may be optionally substituted with substituents selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy and halogeno;

[0011] R⁴ represents a C₆-C₁₀ aryl group which may be optionally substituted with substituents selected from the group consisting of C₁-C₆ alkyl, halogeno C₁-C₆ alkyl, C₁-C₆ alkoxy, halogeno C₁-C₆ alkoxy and halogeno;

[0012] A represents an imino group, an oxygen atom or a sulfur atom;

[0013] In the formula (I) described above:

[0014] The C₁-C₆ alkyl group in the definition of R² or the C₁-C₆ alkyl moiety included in the definition of R¹, R³ or R⁴ is, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl t-butyl, pentyl or hexyl group; preferably a C₁-C₄ alkyl group; more preferably a methyl or ethyl group; and most preferably a methyl group.

[0015] The C₂-C₆ alkenyl group or C₂-C₆ alkenyl moiety of the halogeno C₂-C₆ alkenyl group in the definition of R¹ is, for example, a vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-pentenyl or 2-hexenyl group; preferably a C₂-C₄ alkenyl group, more preferably a C₃-C₄ alkenyl group; still more preferably a 2-propenyl or 2-butenyl group; and most preferably a 2-butenyl group.

[0016] A typical example of a halogeno C₂-C₆ alkenyl group in the definition of R¹ is, for example, a 2,2-difluorovinyl, 3-fluoro-2-propenyl, 3-chloro-2-propenyl, 3-bromo-2-propenyl, 3-iodo-2-propenyl, 3,3-difluoro-2-propenyl, 2,3-dichloro-2-propenyl, 3,3-dichloro-2-propenyl, 2,3-dibromo-2-propenyl, 3,3-dibromo-2-propenyl, 4,4,4-trifluoro-2-butenyl, 5-fluoro-2-pentenyl or 6-fluoro-2-hexenyl group; preferably a 3-chloro-2-propenyl, 3,3-difluoro-2-propenyl, 3,3-dichloro-2-propenyl or 4,4,4-trifluoro-2-butenyl group; and more preferably a 3-chloro-2-propenyl, 3,3-difluoro-2-propenyl or 3,3-dichloro-2-propenyl group.

[0017] The C₃-C₇ cycloalkyl moiety of the C₃-C₇ cycloalkyl group which may be optionally substituted with a C₁-C₆ alkyl group or of the C₃-C₇ cycloalkyl-C₁-C₆ alkyl group which may be optionally substituted with a C₁-C₆ alkyl group in the definition of R¹ is, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group; preferably a C₃-C₆ cycloalkyl group; more preferably a cyclopropyl, cyclopentyl or cyclohexyl group; and most preferably a cyclopropyl group.

[0018] A typical example of the C₃-C₇ cycloalkyl group which may be optionally substituted with a C₁-C₆ alkyl group in the definition of R¹ is, for example, a cyclopropyl, 2-methylcyclopropyl, 2-ethylcyclopropyl, 2-propylcyclopropyl, 2-hexylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, cyclopentyl, 2-methylcyclopentyl, 2-ethylcyclopentyl, cyclohexyl, 2-methylcyclohexyl or cycloheptyl group; preferably a cyclopropyl, 2-methylcyclopropyl, 2-ethylcyclopropyl, cyclobutyl, cyclopentyl, 2-methylcyclopentyl, cyclohexyl or 2-methylcyclohexyl group; more preferably a cyclopropyl, 2-methylcyclopropyl, cyclopentyl, 2-methylcyclopentyl, cyclohexy or 2-methylcyclohexyl group; and most preferably a cyclopropyl or 2-methylcyclopropyl group.

[0019] A typical example of the C₃-C₇ cycloalkyl-C₁-C₆ alkyl group which may be optionally substituted with a C₁-C₆ alkyl group in the definition of R¹ is, for example, a cyclopropylmethyl, 2-cyclopropylethyl, 2-methylcyclopropylmethyl, 2-(2-methylcyclopropyl)ethyl, 3-(2-methylcyclopropyl)propyl, 6-(2-methylcyclopropyl)hexyl, 2-ethylcyclopropylmethyl, 2-propylcyclopropylmethyl, 2-hexylcyclopropylmethyl, cyclobutylmethyl, 2-methylcyclobutylmethyl, cyclopentylmethyl, 2-cyclopentylethyl, 2-methylcyclopentylmethyl, 2-(2-methylcyclopentyl)ethyl, 2-ethylcyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl, 2-methylcyclohexylmethyl, 2-(2-methylcyclohexyl)ethyl or cycloheptylmethyl group; preferably a cyclopropylmethyl, 2-cyclopropylethyl, 2-methylcyclopropylmethyl, 2-(2-methylcyclopropyl)ethyl, 2-ethylcyclopropylmethyl, cyclobutylmethyl, 2-methylcyclobutylmethyl, cyclopentylmethyl, 2-methylcyclopentylmethyl, cyclohexylmethyl or 2-methylcyclohexylmethyl group; more preferably a cyclopropylmethyl, 2-methylcyclopropylmethyl, 2-ethylcyclopropylmethyl, cyclobutylmethyl, 2-methylcyclobutylmethyl, cyclopentylmethyl or 2-methylcyclohexylmethyl group; more preferably a cyclopropylmethyl, 2-methylcyclopropylmethyl, cyclopentylmethyl or 2-methylcyclohexylmethyl group; still more preferably a cyclopropylmethyl or 2-methylcyclopropylmethyl group; and most preferably a 2-methylcyclopropylmethyl group.

[0020] The C₂-C₆ aliphatic acyl moiety of the C₂-C₆ aliphatic acyloxymethyl group in the definition of R³ is, for example, an acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl or hexanoyl group; preferably a C₂-C₄ aliphatic acyl group; more preferably a C₂-C₃ aliphatic acyl group; and most preferably an acetyl group.

[0021] The C₁-C₆ alkoxy moiety of a substituent of the aryl group or a C₁-C₆ alkoxy moiety of the halogeno C₁-C₆ alkoxy group of a substituent of the aryl group in the definition of R³ and R⁴ or the C₁-C₆ alkoxy moiety of the C₁-C₆ alkoxycarbonyloxymethyl group and the C₁-C₆ alkoxycarbonyl group in the definition of R³ is, for example, a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy or hexyloxy group; preferably a C₁-C₄ alkoxy group; more preferably a methoxy or ethoxy group; and most preferably a methoxy group.

[0022] The halogen atom included in the definition of R¹, R³ and R⁴ is, for example, a fluorine, chlorine, bromine or iodine atom; preferably a fluorine, chlorine or bromine atom; more preferably a fluorine or chlorine atom.

[0023] The C₆-C₁₀ aryl moiety of the optionally substituted C₆-C₁₀ aryl moiety in the definition of R³ or of the optionally substituted C₆-C₁₀ aryl group in the definition of R⁴ is, for example, a phenyl or naphthyl group; preferably a phenyl group.

[0024] The number of the substitutents on the aryl group is, for example from 1 to 5; preferably from 1 to 3; more preferably 1 or 2; and most preferably one.

[0025] The preferred C₆-C₁₀ aryl moiety which may be optionally substituted with substituents selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy and halogeno in the definition of R³ is, for example, a phenyl, methylphenyl, dimethylphenyl, methoxyphenyl, dimethoxyphenyl, fluorophenyl, chlorophenyl, bromophenyl, difluorophenyl, chlorofluorophenyl, dichlorophenyl, naphthyl, methylnaphtyl, methoxynaphthyl, fluoronaphthyl, chloronaphthyl or bromonaphthyl group; more preferably a phenyl, methylphenyl, methoxyphenyl, fluorophenyl or chlorophenyl group; most preferably a phenyl or methylphenyl group.

[0026] The preferred C₆-C₁₀ aryl group which may be optionally substituted with substituents selected from the group consisting of C₁-C₆ alkyl, halogeno C₁-C₆ alkyl, C₁-C₆ alkoxy, halogeno C₁-C₆ alkoxy, and halogeno in the definition of R⁴ is, for example, a phenyl, methylphenyl, trifluoromethylphenyl, methoxyphenyl, trifluoromethoxyphenyl, difluoromethoxyphenyl, fluorophenyl, chlorophenyl, bromophenyl, difluorophenyl, chlorofluorophenyl, dichlorophenyl, trifluorophenyl, trichlorophenyl, naphthyl, methylnaphtyl, methoxynaphthyl, fluoronaphthyl, chloronaphthyl or bromonaphthyl group; more preferably a phenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4-difluoromethoxyphenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-chlorophenyl, 4-bromophenyl, 2,4- or 2,6-difluorophenyl, 4-chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl, 2,4- or 2,6-dichlorophenyl, 2,4,6-trifluorophenyl or 2,4,6-trichlorophenyl group; still more preferably a 4-fluorophenyl, 4-chlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl or 2,6-dichlorophenyl group; and most preferably a 4-fluorophenyl, 2,4-difluorophenyl or 4-chlorophenyl group.

[0027] The preferred group A is an oxygen atom or a sulfur atom; more preferably an oxygen atom.

[0028] The compound of formula (I) in this invention can exist as an optical isomer due to an asymmetric carbon atom(s) or as a geometrical isomer due to a double bond(s) or to ring structure. The present invention encompasses a single isomer and mixtures of such isomers.

[0029] The pharmaceutically acceptable salts of compounds of formula (I) are acid addition salts. Examples of such salt are, for example, a hydrohalogenic acid salt such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; a nitrate; a perchlorate; a sulfate; a phosphate; a carbonate; a C₁-C₆ alkylsulfonate which may be optionally substituted with fluorine atoms, such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, pentafluoroethanesulfonate, propanesulfonate, butanesulfonate, pentanesulfonate, hexanesulfonate; a C₆-C₁₀ arylsulfonate such as benzenesulfonate, p-toluenesulfonate; a carboxylate such as acetate, propionate, lactate, benzoate, fumarate, maleate, succinate, citrate, tartrate, oxalate, malonate; or an amino acid salt such as glutamate or aspartate; preferably a hydrochloride, sulfate or carboxylate and most preferably a hydrochloride.

[0030] The compounds of formula (I) in this invention or salts thereof can exist as hydrates. The present invention encompasses such hydrates.

[0031] Preferred compounds of formula (I) are:

[0032] (1) a compound wherein R¹ is a C₂-C₄ alkenyl group, a C₃-C₄ alkenyl group substituted with fluoro or chloro, a C₃-C₆ cycloalkyl group which may be optionally substituted with C₁-C₂ alkyl or a C₃-C₆ cycloalkyl-C₁-C₂ alkyl group which may be substituted with C₁-C₂ alkyl;

[0033] (2) a compound wherein R¹ is a C₃-C₄ alkenyl group, a 3-chloro-2-propenyl group, a 3,3-difluoro-2-propenyl group, a 3,3-dichloro-2-propenyl group, a cyclopropyl group, a 2-methylcyclopropyl group, a 2-ethylcyclopropyl group, a cyclobutyl group, a cyclopentyl group, a 2-methylcyclopentyl group, a cyclohexyl group, a 2-methylcyclohexyl group, a cyclopropylmethyl group, a 2-methylcyclopropylmethyl group, a 2-ethylcyclopropylmethyl group, a cyclobutylmethyl group, a 2-methylcyclobutylmethyl group, a cyclopentylmethyl group or a 2-methylcyclohexylmethyl group;

[0034] (3) a compound wherein R¹ is a 2-propenyl group, a 2-butenyl group, a cyclopropyl group, a 2-methylcyclopropyl group, a cyclopentyl group, a 2-methylcyclopentyl group, a cyclohexyl group, a 2-methylcyclohexyl group, a cyclopropylmethyl group, a 2-methylcyclopropylmethyl group, a cyclopentylmethyl group or a 2-methylcyclohexylmethyl group;

[0035] (4) a compound wherein R¹ is a 2-propenyl group, a 2-butenyl group, a cyclopropyl group, a 2-methylcyclopropyl group, a cyclopropylmethyl group or a 2-methylcyclopropylmethyl group;

[0036] (5) a compound wherein R¹ is a 2-butenyl group, a cyclopropylmethyl group or a 2-methylcyclopropylmethyl group;

[0037] (6) a compound wherein R² is a C₁-C₄ alkyl group;

[0038] (7) a compound wherein R² is a C₁-C₂ alkyl group;

[0039] (8) a compound wherein R² is a methyl group;

[0040] (9) a compound wherein R³ is a hydroxymethyl group, a C₂-C₆ aliphatic acyloxymethyl group, a benzoyloxymethyl group which may be optionally substituted with methyl, methoxy, fluoro or chloro, a C₁-C₄ alkoxycarbonyloxymethyl group, a formyl group, a carboxyl group, a C₁-C₄ alkoxycarbonyl group or a phenyloxycarbonyl group which may be optionally substituted with methyl, methoxy, fluoro or chloro;

[0041] (10) a compound wherein R³ is a hydroxymethyl group, a C₂-C₆ aliphatic acyloxymethyl group, a benzoyloxymethyl group, a C₁-C₂ alkoxycarbonyloxymethyl group, a formyl group, a carboxyl group, a C₁-C₂ alkoxycarbonyl group or a phenyloxycarbonyl group;

[0042] (11) a compound wherein R³ is a hydroxymethyl group, a C₂-C₄ aliphatic acyloxymethyl group, a C₁-C₂ alkoxycarbonyloxymethyl group, a formyl group, a carboxyl group or a C₁-C₂ alkoxycarbonyl group;

[0043] (12) a compound wherein R³ is a hydroxymethyl group, a C₂-C₃ aliphatic acyloxymethyl group, a formyl group or a carboxyl group;

[0044] (13) a compound wherein R³ is a hydroxymethyl group or an acetoxymethyl group;

[0045] (14) a compound wherein R⁴ is a phenyl group which is substituted with 1 to 3 substituents selected from the group consisting of C₁-C₄ alkyl, halogeno C₁-C₄ alkyl, C₁-C₄ alkoxy, halogeno C₁-C₄ alkoxy, fluoro, chloro and bromo;

[0046] (15) a compound wherein R⁴ is a phenyl group which is substituted with 1 to 3 substituents selected from the group consisting of methyl, trifluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, fluoro, chloro and bromo;

[0047] (16) a compound wherein R⁴ is a phenyl group which is substituted at the position(s) selected from the group consisting of 2-, 4- and 6-position of the phenyl group with 1 or 2 substituents selected from the group consisting of fluoro and chloro;

[0048] (17) a compound wherein R⁴ is a phenyl group which is substituted at the 4-position, 2,4-positions or 2,6-positions of the phenyl group with 1 or 2 substituents selected from the group consisting of fluoro and chloro;

[0049] (18) a compound wherein A is an oxygen atom or a sufur atom; and

[0050] (19) a compound wherein A is an oxygen atom.

[0051] In each group of compounds (1)-(5), (6)-(8), (9)-(13), (14)-(17), or (18)-(19) described above, the larger the number of the compound is, the more preferable the compound, (similarly in the group of compounds (20)-(24) described below). Compounds wherein R¹, R², R³, R⁴ and A are optionally selected from groups of compounds (1)-(5), (6)-(8), (9)-(13), (14)-(17), and (18)-(19), respectively, are a preferable.

[0052] Such compounds are as follows for example:

[0053] (20) a compound wherein R¹ is a C₂-C₄ alkenyl group, a C₃-C₄ alkenyl group substituted with fluoro or chloro, a C₃-C₆ cycloalkyl group which may be optionally substituted with C₁-C₂ alkyl or a C₃-C₆ cycloalkyl-C₁-C₂ alkyl group which may be substituted with C₁-C₂ alkyl,

[0054] R² is a C₁-C₄ alkyl group,

[0055] R³ is a hydroxymethyl group, a C₂-C₆ aliphatic acyloxymethyl group, a benzoyloxymethyl group which may be optionally substituted with methyl, methoxy, fluoro or chloro, a C₁-C₄ alkoxycarbonyloxymethyl group, a formyl group, a carboxyl group, a C₁-C₄ alkoxycarbonyl group or a phenyloxycarbonyl group which may be optionally substituted with methyl, methoxy, fluoro or chloro,

[0056] R⁴ is a phenyl group which is substituted with 1 to 3 substituents selected from the group consisting of C₁-C₄ alkyl, halogeno C₁-C₄ alkyl, C₁-C₄ alkoxy, halogeno-C₁-C₄ alkoxy, fluoro, chloro and bromo,

[0057] A is an oxygen atom or a sufur atom;

[0058] (21) a compound wherein R¹ is a C₃-C₄ alkenyl group, a 3-chloro-2-propenyl group, a 3,3-difluoro-2-propenyl, a 3,3-dichloro-2-propenyl group, a cyclopropyl group, a 2-methylcyclpropyl group, a 2-ethylcyclopropyl group, a cyclobutyl group, a cyclopentyl group, a 2-methylcyclopentyl group, a cyclohexyl group, a 2-methylcyclohexyl group, a cyclopropylmethyl group, a 2-methylcyclopropylmethyl group, a 2-ethylcyclopropylmethyl group, a cyclobutylmethyl group, a 2-methylcyclobutylmethyl group, a cyclopentylmethyl group or a 2-methylcyclohexylmethyl group,

[0059] R² is a C₁-C₄ alkyl group,

[0060] R³ is a hydroxymethyl group, a C₂-C₆ aliphatic acyloxymethyl group, a benzoyloxymethyl group, a C₁-C₂ alkoxycarbonyloxymethyl group, a formyl group, a carboxyl group, a C₁-C₂ alkoxycarbonyl group or a phenyloxycarbonyl group,

[0061] R⁴ is a phenyl group which is substituted with 1 to 3 substituents selected from the group consisting of methyl, trifluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, fluoro, chloro and bromo,

[0062] A is an oxygen atom or a sulfur atom;

[0063] (22) a compound wherein R¹ is a 2-propenyl group, a 2-butenyl group, a cyclopropyl group, a 2-methylcyclopropyl group, a cyclopentyl group, a 2-methylcyclopentyl group, a cyclohexyl group, a 2-methylcyclohexyl group, a cyclopropylmethyl group, a 2-methylcyclopropylmethyl group, a cyclopentylmethyl group or a 2-methylcyclohexylmethyl group,

[0064] R² is a C₁-C₂ alkyl group,

[0065] R³ is a hydroxymethyl group, a C₂-C₄ aliphatic acyloxymethyl group, a C₁-C₂ alkoxycarbonyloxymethyl group, a formyl group, a carboxyl group or a C₁-C₂ alkoxycarbonyl group,

[0066] R⁴ is a phenyl group which is substituted at the position(s) selected from the group consisting of 2-, 4- and 6-position of the phenyl group with 1 or 2 substituents selected from the group consisting of fluoro and chloro,

[0067] A is an oxygen atom;

[0068] (23) a compound wherein R¹ is a 2-propenyl group, a 2-butenyl group, a cyclopropyl group, a 2-methylcyclopropyl group, a cyclopropylmethyl group or a 2-methylcyclopropylmethyl group,

[0069] R² is a C₁-C₂ alkyl group,

[0070] R³ is a hydroxymethyl group, a C₂-C₃ aliphatic acyloxymethyl group, a formyl group or a carboxyl group,

[0071] R⁴ is a phenyl group which is substituted at the position(s) selected from the group consisting of 2-, 4- and 6-position of the phenyl group with 1 or 2 substituents selected from the group consisting of fluoro and chloro,

[0072] A is an oxygen atom; and

[0073] (24) a compound wherein R¹ is a 2-butenyl group, a cyclopropylmethyl group of a 2-methylcyclopropylmethyl group

[0074] R² is a methyl group,

[0075] R³ is a hydroxymethyl group or an acetoxymethyl group,

[0076] R⁴ is a phenyl group which is substituted at the 4position, 2,4-positions or, 2,6-positions of the phenyl group with 1 or 2 substituents selected from the group consisting of fluoro and chloro,

[0077] A is an oxygen atom.

[0078] Preferred compounds of formula (I) can be exemplified in Table 1. TABLE 1

(I) Exemp. Comp. No. R¹ R² R³ A R⁴ 1 CH═CHCH₃ Me CH₂OH O Ph 2 CH₂CH═CH₂ Me CH₂OH O Ph 3 CH₂C(CH₃)CH₂ Me CH₂OH O Ph 4 CH₂CH═CHCH₃ Me CH₂OH O Ph 5 CH₂CH═CF₂ Me CH₂OH O Ph 6 Pr^(c) Me CH₂OH O Ph 7 2-MePr^(c) Me CH₂OH O Ph 8 CH₂Pr^(c) Me CH₂OH O Ph 9 CH₂(2-MePr^(c)) Me CH₂OH O Ph 10 CH₂Bu^(c) Me CH₂OH O Ph 11 CH₂Pn^(c) Me CH₂OH O Ph 12 CH₂Hx^(c) Me CH₂OH O Ph 13 CH═CHCH₂ Me CH₂OH O 2-FPh 14 CH₂CH═CH₂ Me CH₂OH O 2-FPh 15 CH₂CH═CHCH₃ Me CH₂OH O 2-FPh 16 CH₂Pr^(c) Me CH₂OH O 2-FPh 17 CH₂(2-MePr^(c)) Me CH₂OH O 2-FPh 18 CH═CH₂ Me CH₂OH O 4-FPh 19 CH═CHCH₃ Me CH₂OH O 4-FPh 20 CH₂CH═CH₂ Me CH₂OH O 4-FPh 21 CH₂C(CH₃)CH₂ Me CH₂OH O 4-FPh 22 CH₂CH═CHCH₃ Me CH₂OH O 4-FPh 23 CH₂CH═CHCH₂CH₃ Me CH₂OH O 4-FPh 24 CH₂CH═CF₂ Me CH₂OH O 4-FPh 25 CH₂CH═CHCl Me CH₂OH O 4-FPh 26 CH₂CH═CHl₂ Me CH₂OH O 4-FPh 27 Pr^(c) Me CH₂OH O 4-FPh 28 2-MePr^(c) Me CH₂OH O 4-FPh 29 Bu^(c) Me CH₂OH O 4-FPh 30 Pn^(c) Me CH₂OH O 4-FPh 31 Hx^(c) Me CH₂OH O 4-FPh 32 CH₂Pr^(c) Me CH₂OH O 4-FPh 33 CH₂(2-MePr^(c)) Me CH₂OH O 4-FPh 34 CH₂CH₂Pr^(c) Me CH₂OH O 4-FPh 35 CH₂Bu^(c) Me CH₂OH O 4-FPh 36 CH₂Pn^(c) Me CH₂OH O 4-FPh 37 CH₂(2-MePn^(c)) Me CH₂OH O 4-FPh 38 CH₂Hx^(c) Me CH₂OH O 4-FPh 39 CH₂(2-MeHx^(c)) Me CH₂OH O 4-FPh 40 CH═CHCH₃ Me CH₂OH O 2,4-diFPh 41 CH₂CHCH₂ Me CH₂OH O 2,4-diFPh 42 CH₂C(CH₃)═CH₂ Me CH₂OH O 2,4-diFPh 43 CH₂CH═CHCH₃ Me CH₂OH O 2,4-diFPh 44 CH₂CH═CF₂ Me CH₂OH O 2,4-diFPh 45 Pr^(c) Me CH₂OH O 2,4-diFPh 46 2-MePr^(c) Me CH₂OH O 2,4-diFPh 47 CH₂Pr^(c) Me CH₂OH O 2,4-diFPh 48 CH₂(2-MePr^(c)) Me CH₂OH O 2,4-diFPh 49 CH₂Bu^(c) Me CH₂OH O 2,4-diFPh 50 CH₂Pn^(c) Me CH₂OH O 2,4-diFPh 51 CH₂Hx^(c) Me CH₂OH O 2,4-diFPh 52 CH═CHCH₃ Me CH₂OH O 2-ClPh 53 CH₂CH═CH₂ Me CH₂OH O 2-ClPh 54 CH₂CH═CHCH₃ Me CH₂OH O 2-ClPh 55 CH₂Pr^(c) Me CH₂OH O 2-ClPh 56 CH₂(2-MePr^(c)) Me CH₂OH O 2-ClPh 57 CH═CHCH₃ Me CH₂OH O 4-ClPh 58 CH₂CH═CH₂ Me CH₂OH O 4-ClPh 59 CH₂CH═CHCH₃ Me CH₂OH O 4-ClPh 60 CH₂Pr^(c) Me CH₂OH O 4-ClPh 61 CH₂(2-MePr^(c)) Me CH₂OH O 4-ClPh 62 CH₂CH═CH₂ Me CH₂OH O 2-F,4-ClPh 63 CH₂CH═CHCH₃ Me CH₂OH O 2-F,4-ClPh 64 CH₂Pr^(c) Me CH₂OH O 2-F,4-ClPh 65 CH₂(2-MePr^(c)) Me CH₂OH O 2-F,4-ClPh 66 CH₂CH═CH₂ Me CH₂OH O 2-Cl,4-FPh 67 CH₂CH═CHCH₃ Me CH₂OH O 2-Cl,4-FPh 68 CH₂Pr^(c) Me CH₂OH O 2-Cl,4-FPh 69 CH₂(2-MePr^(c)) Me CH₂OH O 2-Cl,4-FPh 70 CH₂CH═CH₂ Me CH₂OH O 2,4-diClPh 71 CH₂CH═CHCH₃ Me CH₂OH O 2,4-diClPh 72 CH₂Pr^(c) Me CH₂OH O 2,4-diClPh 73 CH₂(2-MePr^(c)) Me CH₂OH O 2,4-diClPh 74 CH═CHCH₃ Me CH₂OAc O Ph 75 CH₂CH═CH₂ Me CH₂OAc O Ph 76 CH₂C(CH₃)═CH₂ Me CH₂OAc O Ph 77 CH₂CH═CHCH₃ Me CH₂OAc O Ph 78 CH₂CH═CF₂ Me CH₂OAc O Ph 79 Pr^(c) Me CH₂OAc O Ph 80 2-MePr^(c) Me CH₂OAc O Ph 81 CH₂Pr^(c) Me CH₂OAc O Ph 82 CH₂(2-MePr^(c)) Me CH₂OAc O Ph 83 CH₂BuC Me CH₂OAc O Ph 84 CH₂Pn^(c) Me CH₂OAc O Ph 85 CH₂Hx^(c) Me CH₂OAc O Ph 86 CH═CHCH₃ Me CH₂OAc O 2-FPh 87 CH₂CH═CH₂ Me CH₂OAc O 2-FPh 88 CH₂CH═CHCH₃ Me CH₂OAc O 2-FPh 89 CH₂Pr^(c) Me CH₂OAc O 2-FPh 90 CH₂(2-MePr^(c)) Me CH₂OAc O 2-FPh 91 CH═CH₂ Me CH₂OAc O 4-FPh 92 CH═CHCH₃ Me CH₂OAc O 4-FPh 93 CH₂CH═CH₂ Me CH₂OAc O 4-FPh 94 CH₂C(CH₃)═CH₂ Me CH₂OAc O 4-FPh 95 CH₂CH═CHCH₃ Me CH₂OAc O 4-FPh 96 CH₂CH═CHCH₂CH₃ Me CH₂OAc O 4-FPh 97 CH₂CHCF₂ Me CH₂OAc O 4-FPh 98 CH₂CH═CHCl Me CH₂OAc O 4-FPh 99 CH₂CH═CCl₂ Me CH₂OAc O 4-FPh 100 Pr^(c) Me CH₂OAc O 4-FPh 101 2-MePr^(c) Me CH₂OAc O 4-FPh 102 Bu^(c) Me CH₂OAc O 4-FPh 103 Pn^(c) Me CH₂OAc O 4-FPh 104 Hx^(c) Me CH₂OAc O 4-FPh 105 CH₂Pr^(c) Me CH₂OAc O 4-FPh 106 CH₂(2-MePr^(c)) Me CH₂OAc O 4-FPh 107 CH₂CH₂Pr^(c) Me CH₂OAc O 4-FPh 108 CH₂Bu^(c) Me CH₂OAc O 4-FPh 109 CH₂Pn^(c) Me CH₂OAc O 4-FPh 110 CH₂(2-MePn^(c)) Me CH₂OAc O 4-FPh 111 CH₂Hx^(c) Me CH₂OAc O 4-FPh 112 CH₂(2-MeHx^(c)) Me CH₂OAc O 4-FPh 113 CH═CHCH₃ Me CH₂OAc O 2,4-diFPh 114 CH₂CH═CH₂ Me CH₂OAc O 2,4-diFPh 115 CH₂C(CH₃)═CH₂ Me CH₂OAc O 2,4-diFPh 116 CH₂CH═CHCH₃ Me CH₂OAc O 2,4-diFPh 117 CH₂CH═CF₂ Me CH₂OAc O 2,4-diFPh 118 Pr^(c) Me CH₂OAc O 2,4-diFPh 119 2-MePr^(c) Me CH₂OAc O 2,4-diFPh 120 CH₂Pr^(c) Me CH₂OAc O 2,4-diFPh 121 CH₂(2-MePr^(c)) Me CH₂OAc O 2,4-diFPh 122 CH₂Bu^(c) Me CH₂OAc O 2,4-diFPh 123 CH₂Pn^(c) Me CH₂OAc O 2,4-diFPh 124 CH₂Hx^(c) Me CH₂OAc O 2,4-diFPh 125 CH═CHCH₃ Me CH₂OAc O 2-ClPh 126 CH₂CH═CH₂ Me CH₂OAc O 2-ClPh 127 CH₂CH═CHCH₃ Me CH₂OAc O 2-ClPh 128 CH₂Pr^(c) Me CH₂OAc O 2-ClPh 129 CH₂(2-MePr^(c)) Me CH₂Oac O 2-ClPh 130 CH═CHCH₃ Me CH₂OAc O 4-ClPh 131 CH₂CH═CH₂ Me CH₂OAc O 4-ClPh 132 CH₂CH═CHCH₃ Me CH₂OAc O 4-ClPh 133 CH₂Pr^(c) Me CH₂OAc O 4-ClPh 134 CH₂(2-MePr^(c)) Me CH₂OAc O 4-ClPh 135 CH₂CH═CH₂ Me CH₂OAc O 2-F,4-ClPh 136 CH₂CH═CHCH₃ Me CH₂OAc O 2-F,4-ClPh 137 CH₂Pr^(c) Me CH₂OAc O 2-F,4-ClPh 138 CH₂(2-MePr^(c)) Me CH₂OAc O 2-F,4-ClPh 139 CH₂CH═CH₂ Me CH₂OAc O 2-CI,4-FPh 140 CH₂CH═CHCH₃ Me CH₂OAc O 2-Cl,4-FPh 141 CH₂Pr^(c) Me CH₂OAc O 2-Cl,4-FPh 142 CH₂(2-MePr^(c)) Me CH₂OAc O 2-Cl,4-FPh 143 CH₂CH═CH₂ Me CH₂OAc O 2,4-diClPh 144 CH₂CH═CHCH₃ Me CH₂OAc O 2,4-diClPh 145 CH₂Pr^(c) Me CH₂OAc O 2,4-diClPh 146 CH₂(2-MePr^(c)) Me CH₂OAc O 2,4-diClPh 147 CH═CHCH₃ Me CH₂OPrp O Ph 148 CH₂CH═CH₂ Me CH₂OPrp O Ph 149 CH₂CH═CHCH₃ Me CH₂OPrp O Ph 150 CH₂CH═CF₂ Me CH₂OPrP O Ph 151 Pr^(c) Me CH₂OPrp O Ph 152 2-MePr^(c) Me CH₂OPrp O Ph 153 CH₂Pr^(c) Me CH₂OPrp O Ph 154 CH₂(2-MePr^(c)) Me CH₂OPrp O Ph 155 CH₂CH═CH₂ Me CH₂OPrp O 2-FPh 156 CH₂CH═CHCH₃ Me CH₂OPrp O 2-FPh 157 CH₂Pr^(c) Me CH₂OPrp O 2-FPh 158 CH₂(2-MePr^(c)) Me CH₂OPrp O 2-FPh 159 CH═CHCH₃ Me CH₂OPrp O 4-FPh 160 CH₂CH═CH₂ Me CH₂OPrp O 4-FPh 161 CH₂CH═CHCH₃ Me CH₂OPrp O 4-FPh 162 CH₂CH═CF₂ Me CH₂OPrp O 4-FPh 163 CH₂CH═CHCl Me CH₂OPrp O 4-FPh 164 Pr^(c) Me CH₂OPrp O 4-FPh 165 2-MePr^(c) Me CH₂OPrp O 4-FPh 166 CH₂Pr^(c) Me CH₂OPrp O 4-FPh 167 CH₂(2-MePr^(c)) Me CH₂OPrp O 4-FPh 168 CH₂Bu^(c) Me CH₂OPrp O 4-FPh 169 CH₂Pn^(c) Me CH₂OPrp O 4-FPh 170 CH₂Hx^(c) Me CH₂OPrp O 4-FPh 171 CH═CHCH₃ Me CH₂OPrp O 2,4-diFPh 172 CH₂CH═CH₂ Me CH₂OPrp O 2,4-diFPh 173 CH₂CH═CHCH₃ Me CH₂OPrp O 2,4-diFPh 174 CH₂CH═CF₂ Me CH₂OPrp O 2,4-diFPh 175 Pr^(c) Me CH₂OPrp O 2,4-diFPh 176 2-MePr^(c) Me CH₂OPrp O 2,4-diFPh 177 CH₂Pr^(c) Me CH₂OPrp O 2,4-diFPh 178 CH₂(2-MePr^(c)) Me CH₂OPrp O 2,4-diFPh 179 CH═CHCH₃ Me CH₂OPrp O 2-ClPh 180 CH₂CH═CH₂ Me CH₂OPrp O 2-ClPh 181 CH₂CH═CHCH₃ Me CH₂OPrp O 2-ClPh 182 CH₂Pr^(c) Me CH₂OPrp O 2-ClPh 183 CH₂(2-MePr^(c)) Me CH₂OPrp O 2-ClPh 184 CH═CHCH₃ Me CH₂OPrp O 4-ClPh 185 CH₂CH═CH₂ Me CH₂OPrp O 4-ClPh 186 CH₂CH═CHCH₃ Me CH₂OPrp O 4-ClPh 187 CH₂Pr^(c) Me CH₂OPrp O 4-ClPh 188 CH₂(2-MePr^(c)) Me CH₂OPrp O 4-ClPh 189 CH₂CH═CH₂ Me CH₂OPrp O 2-F,4-ClPh 190 CH₂CH═CHCH₃ Me CH₂OPrp O 2-F,4-ClPh 191 CH₂Pr^(c) Me CH₂OPrp O 2-F,4-ClPh 192 CH₂(2-MePr^(c)) Me CH₂OPrp O 2-F,4-ClPh 193 CH₂CH═CH₂ Me CH₂OPrp O 2-Cl,4-FPh 194 CH₂CH═CH═CH₃ Me CH₂OPrp O 2-Cl,4-FPh 195 CH₂Pr^(c) Me CH₂OPrp O 2-Cl,4-FPh 196 CH₂(2-MePr^(c)) Me CH₂OPrp O 2-Cl,4-FPh 197 CH₂CH═CH₂ Me CH₂OPrp O 2,4-diClPh 198 CH₂CH═CHCH₃ Me CH₂OPrp O 2,4-diClPh 199 CH₂Pr^(c) Me CH₂OPrp O 2,4-diClPh 200 CH₂(2-MePr^(c)) Me CH₂OPrp O 2,4-diClPh 201 CH₂CH═CH₂ Me CH₂OPrp O Ph 202 CH₂CH═CHCH₃ Me CH₂OBur O Ph 203 CH₂Pr^(c) Me CH₂OBur O Ph 204 CH₂(2-MePr^(c)) Me CH₂OBur O Ph 205 CH₂CH═CH₂ Me CH₂OBur O 2-FPh 206 CH₂CH═CHCH₃ Me CH₂OBur O 2-FPh 207 CH₂Pr^(c) Me CH₂OBur O 2-FPh 208 CH₂(2-MePr^(c)) Me CH₂OBur O 2-FPh 209 CH═CHCH₃ Me CH₂OBur O 4-FPh 210 CH₂CH═CH₂ Me CH₂OBur O 4-FPh 211 CH₂CH═CHC₃ Me CH₂OBur O 4-FPh 212 CH₂CH═CF₂ Me CH₂OBur O 4-FPh 213 Pr^(c) Me CH₂OBur O 4-FPh 214 2-MePr^(c) Me CH₂OBur O 4-FPh 215 CH₂Pr^(c) Me CH₂OBur O 4-FPh 216 CH₂(2-MePr^(c)) Me CH₂OBur O 4-FPh 217 CH₂Bu^(c) Me CH₂OBur O 4-FPh 218 CH₂Pn^(c) Me CH₂OBur O 4-FPh 219 CH₂Hx^(c) Me CH₂OBur O 4-FPh 220 CH₂CH═CH₂ Me CH₂OBur O 2,4-diFPh 221 CH₂CH═CHCH₃ Me CH₂OBur O 2,4-diFPh 222 Pr^(c) Me CH₂OBur O 2,4-diFPh 223 2-MePr^(c) Me CH₂OBur O 2,4-diFPh 224 CH₂Pr^(c) Me CH₂OBur O 2,4-diFPh 225 CH₂(2-MePr^(c)) Me CH₂OBur O 2,4-diFPh 226 CH₂CH═CH₂ Me CH₂OBur O 2-ClPh 227 CH₂CH═CHCH₃ Me CH₂OBur O 2-ClPh 228 CH₂Pr^(c) Me CH₂OBur O 2-ClPh 229 CH₂(2-MePr^(c)) Me CH₂OBur O 2-ClPh 230 CH₂CH═CH₂ Me CH₂OBur O 4-ClPh 231 CH₂CH═CHCH₃ Me CH₂OBur O 4-ClPh 232 CH₂Pr^(c) Me CH₂OBur O 4-ClPh 233 CH₂(2-MePr^(c)) Me CH₂OBur O 4-ClPh 234 CH₂CH═CH₂ Me CH₂OBur O 2-F,4-ClPh 235 CH₂CH═CHCH₃ Me CH₂OBur O 2-F,4-ClPh 236 CH₂Pr^(c) Me CH₂OBur O 2-F,4-ClPh 237 CH₂(2-MePr^(c)) Me CH₂OBur O 2-F,4-ClPh 238 CH₂CH═CH₂ Me CH₂OBur O 2-Cl,4-FPh 239 CH₂CH═CHCH₃ Me CH₂OBur O 2-Cl,4-FPh 240 CH₂Pr^(c) Me CH₂OBur O 2-Cl,4-FPh 241 CH₂(2-MePr^(c)) Me CH₂OBur O 2-Cl,4-FPh 242 CH₂CH═CH₂ Me CH₂OBur O 2,4-diClPh 243 CH₂CH═CHCH₃ Me CH₂OBur O 2,4-diClPh 244 CH₂Pr^(c) Me CH₂OBur O 2,4-diClPh 245 CH₂(2-MePr^(c)) Me CH₂OBur O 2,4-diClPh 246 CH₂CH═CH₂ Me CH₂OCOPh O Ph 247 CH₂Pr^(c) Me CH₂OCOPh O Ph 248 CIH₂(2-MePr^(c)) Me CH₂OCOPh O Ph 249 CH₂(2-MePr^(c)) Me CH₂OCO(4-Me)Ph O Ph 250 CH₂CH═CH₂ Me CH₂OCOPh O 2-FPh 251 CH₂Pr^(c) Me CH₂OCOPh O 2-FPh 252 CH₂(2-MePr^(c)) Me CH₂OCOPh O 2-FPh 253 CH₂(2-MePr^(c)) Me CH₂OCO(4-Me)Ph) O 2-FPh 254 CH═CHCH₃ Me CH₂OCOPh O 4-FPh 255 CH₂CH═CH₂ Me CH₂OCOPh O 4-FPh 256 CH₂CH═CH₂ Me CH₂OCO(4-Me)Ph O 4-FPh 257 CH₂CH═CHCH₃ Me CH₂OCOPh O 4-FPh 258 CH₂CHCF₂ Me CH₂OCOPh O 4-FPh 259 Pr^(c) Me CH₂OCOPh O 4-FPh 260 2-MePr^(c) Me CH₂OCOPh O 4-FPh 261 CH₂Pr^(c) Me CH₂OCOPh O 4-FPh 262 CH₂Pr^(c) Me CH₂OCO(4-Me)Ph O 4-FPh 263 CH₂(2-MePr^(c)) Me CH₂OCOPh O 4-FPh 264 CH₂(2-MePr^(c)) Me CH₂OC0(4-Me)Ph O 4-FPh 265 CH₂(2-MePr^(c)) Me CH₂OCO(4- O 4-FPh MeO)Ph 266 CH₂(2-MePr^(c)) Me CH₂OCO(4-Cl)Ph O 4-FPh 267 CH₂(2-MePr^(c)) Me CH₂OCO(4-F)Ph O 4-FPh 268 CH₂BuC Me CH₂OCOPh O 4-FPh 269 CH₂Pn^(c) Me CH₂OCOPh O 4-FPh 270 CH₂Hx^(c) Me CH₂OCOPh O 4-FPh 271 CH₂CH═CH₂ Me CH₂OCOPh O 2,4-diFPh 272 CH₂CH═CH₂ Me CH₂OCO(4-Me)Ph O 2,4-diFPh 273 CH₂CH═CHCH₃ Me CH₂OCOPh O 2,4-diFPh 274 Pr^(c) Me CH₂OCOPh O 2,4-diFPh 275 CH₂Pr^(c) Me CH₂OCOPh O 2,4-diFPh 276 CH₂(2-MePr^(c)) Me CH₂OCOPh O 2,4-diFPh 277 CH₂(2-MePr^(c)) Me CH₂OCO(4-Me)Ph O 2,4-diFPh 278 CH₂CH═CH₂ Me CH₂OCOPh O 2-ClPh 279 CH₂Pr^(c) Me CH₂OCOPh O 2-ClPh 280 CH₂(2-MePr^(c)) Me CH₂OCOPh O 2-ClPh 281 CH₂(2-MePr^(c)) Me CH₂OCO(4-Me)Ph O 2-ClPh 282 CH₂CH═CH₂ Me CH₂OCOPh O 4-ClPh 283 CH₂CH═CHCH₃ Me CH₂OCOPh O 4-ClPh 284 CH₂Pr^(c) Me CH₂OCOPh O 4-ClPh 285 CH₂(2-MePr^(c)) Me CH₂OCOPh O 4-ClPh 286 CH₂(2-MePr^(c)) Me CH₂OCO(4-Me)Ph O 4-ClPh 287 CH₂CH═CHCH₃ Me CH₂OCOPh O 2-F,4-ClPh 288 CH₂Pr^(c) Me CH₂OCOPh O 2-F,4-ClPh 289 CH₂(2-MePr^(c)) Me CH₂OCOPh O 2-F,4-ClPh 290 CH₂(2-MePr^(c)) Me CH₂OCO(4-Me)Ph O 2-F,4-ClPh 291 CH₂CH═CHCH₃ Me CH₂OCOPh O 2-Cl,4-FPh 292 CH₂Pr^(c) Me CH₂OCOPh O 2-Cl,4-FPh 293 CH₂(2-MePr^(c)) Me CH₂OCOPh O 2-Cl,4-FPh 294 CH₂(2-MePr^(c)) Me CH₂OCO(4-Me)Ph O 2-Cl,4-FPh 295 CH₂CH═CHCH₃ Me CH₂OCOPh O 2,4-diClPh 296 CH₂Pr^(c) Me CH₂OCOPh O 2,4-diClPh 297 CH₂(2-MePr^(c)) Me CH₂OCOPh O 2,4-diClPh 298 CH₂(2-MePr^(c)) Me CH₂OCO(4-Me)Ph O 2,4-diClPh 299 CH₂CH═CHCH₃ Me CH₂OCO₂Me O Ph 300 CH₂Pr^(c) Me CH₂OCO₂Me O Ph 301 CH₂(2-MePr^(c)) Me CH₂OCO₂Me O Ph 302 CH₂CH═CH₃ Me CH₂OCO₂Me O 2-FPh 303 CH₂Pr^(c) Me CH₂OCO₂Me O 2-FPh 304 CH₂(2-MePr^(c)) Me CH₂OCO₂Me O 2-FPh 305 CH═CHCH₃ Me CH₂OCO₂Me O 4-FPh 306 CH₂CH═CH₂ Me CH₂OCO₂Me O 4-FPh 307 CH₂CH═CHCH₃ Me CH₂OCO₂Me O 4-FPh 308 Pr^(c) Me CH₂OCO₂Me O 4-FPh 309 2-MePr^(c) Me CH₂OCO₂Me O 4-FPh 310 CH₂Pr^(c) Me CH₂OCO₂Me O 4-FPh 311 CH₂(2-MePr^(c)) Me CH₂OCO₂Me O 4-FPh 312 CH₂Bu^(c) Me CH₂OCO₂Me O 4-FPh 313 CH₂Pn^(c) Me CH₂OCO₂Me O 4-FPh 314 CH₂Hx^(c) Me CH₂OCO₂Me O 4-FPh 315 CH₂CH═CHCH₃ Me CH₂OCO₂Me O 2,4-diFPh 316 CH₂Pr^(c) Me CH₂OCO₂Me O 2,4-diFPh 317 CH₂(2-MePr^(c)) Me CH₂OCO₂Me O 2,4-diFPh 318 CH₂CH═CHCH₃ Me CH₂OCO₂Me O 2-ClPh 319 CH₂Pr^(c) Me CH₂OCO₂Me O 2-ClPh 320 CH₂(2-MePr^(c)) Me CH₂OCO₂Me O 2-ClPh 321 CH₂CH═CHCH₃ Me CH₂OCO₂Me O 4-ClPh 322 CH₂Pr^(c) Me CH₂OCO₂Me O 4-ClPh 323 CH₂(2-MePr^(c)) Me CH₂OCO₂Me O 4-ClPh 324 CH₂CH═CHCH₃ Me CH₂OCO₂Me O 2-F,4-ClPh 325 CH₂Pr^(c) Me CH₂OCO₂Me O 2-F,4-ClPh 326 CH₂(2-MePr^(c)) Me CH₂OCO₂Me O 2-F,4-ClPh 327 CH₂CH═CHCH₃ Me CH₂OCO₂Me O 2-Cl,4-FPh 328 CH₂Pr^(c) Me CH₂OCO₂Me O 2-Cl,4-FPh 329 CH₂(2-MePr^(c)) Me CH₂OCO₂Me O 2-Cl,4-FPh 330 CH₂CH═CHCH₃ Me CH₂OCO₂Me O 2,4-diClPh 331 CH₂Pr^(c) Me CH₂OCO₂Me O 2,4-diClPh 332 CH₂(2-MePr^(c)) Me CH₂OCO₂Me O 2,4-diClPh 333 CH₂CH═CHCH₃ Me CH₂OCO₂Et O Ph 334 CH₂Pr^(c) Me CH₂OCO₂Et O Ph 335 CH₂(2-MePr^(c)) Me CH₂OCO₂Et O Ph 336 CH₂CH═CHCH₃ Me CH₂OCO₂Et O 2-FPh 337 CH₂Pr^(c) Me CH₂OCO₂Et O 2-FPh 338 CH₂(2-MePr^(c)) Me CH₂OCO₂Et O 2-FPh 339 CH═CHCH₃ Me CH₂OCO₂Et O 4-FPh 340 CH₂CH═CH₂ Me CH₂OCO₂Et O 4-FPh 341 CH₂CH═CHCH₃ Me CH₂OCO₂Et O 4-FPh 342 Pr^(c) Me CH₂OCO₂Et O 4-FPh 343 2-MePr^(c) Me CH₂OCO₂Et O 4-FPh 344 CH₂Pr^(c) Me CH₂OCO₂Et O 4-FPh 345 CH₂(2-MePr^(c)) Me CH₂OCO₂Et O 4-FPh 346 CH₂Bu^(c) Me CH₂OCO₂Et O 4-FPh 347 CH₂Pn^(c) Me CH₂OCO₂Et O 4-FPh 348 CH₂Hx^(c) Me CH₂OCO₂Et O 4-FPh 349 CH₂CH═CHCH₃ Me CH₂OCO₂Et O 2,4-diFPh 350 CH₂Pr^(c) Me CH₂OCO₂Et O 2,4-diFPh 351 CH₂(2-MePr^(c)) Me CH₂OCO₂Et O 2,4-diFPh 352 CH₂CH═CHCH₃ Me CH₂OCO₂Et O 2-ClPh 353 CH₂Pr^(c) Me CH₂OCO₂Et O 2-ClPh 354 CH₂(2-MePr^(c)) Me CH₂OCO₂Et O 2-ClPh 355 CH₂CH═CHCH₃ Me CH₂OCO₂Et O 4-ClPh 356 CH₂Pr^(c) Me CH₂OCO₂Et O 4-ClPh 357 CH₂(2-MePr^(c)) Me CH₂OCO₂Et O 4-ClPh 358 CH₂CH═CHCH₃ Me CH₂OCO₂Et O 2-F,4-ClPh 359 CH₂Pr^(c) Me CH₂OCO₂Et O 2-F,4-ClPh 360 CH₂(2-MePr^(c)) Me CH₂OCO₂Et O 2-F,4-ClPh 361 CH₂CH═CHCH₃ Me CH₂OCO₂Et O 2-Cl,4-FPh 362 CH₂Pr^(c) Me CH₂OCO₂Et O 2-Cl,4-FPh 363 CH₂(2-MePr^(c)) Me CH₂OCO₂Et O 2-Cl,4-FPh 364 CH₂CH═CHCH₃ Me CH₂OCO₂Et O 2,4-diClPh 365 CH₂Pr^(c) Me CH₂OCO₂Et O 2,4-diClPh 366 CH₂(2-MePr^(c)) Me CH₂OCO₂Et O 2,4-diClPh 367 CH₂CH═CHCH₃ Me CH₂OCO₂Pr O Ph 368 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr O Ph 369 CH₂CH═CHCH₃ Me CH₂OCO₂Pr O 2-FPh 370 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr O 2-FPh 371 CH₂CH═CHCH₃ Me CH₂OCO₂Pr O 4-FPh 372 CH₂Pr^(c) Me CH₂OCO₂Pr O 4-FPh 373 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr O 4-FPh 374 CH₂Pn^(c) Me CH₂OCO₂Pr O 4-FPh 375 CH₂Hx^(c) Me CH₂OCO₂Pr O 4-FPh 376 CH₂CH═CHCH₃ Me CH₂OCO₂Pr O 2,4-diFPh 377 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr O 2,4-diFPh 378 CH₂CH═CHCH₃ Me CH₂OCO₂Pr O 2-ClPh 379 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr O 2-ClPh 380 CH₂CH═CHCH₃ Me CH₂OCO₂Pr O 4-ClPh 381 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr O 4-ClPh 382 CH₂CH═CHCH₃ Me CH₂OCO₂Pr O 2-F,4-ClPh 383 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr O 2-F,4-ClPh 384 CH₂CH═CHCH₃ Me CH₂OCO₂Pr O 2-Cl,4-FPh 385 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr O 2-Cl,4-FPh 386 CH₂CH═CHCH₃ Me CH₂OCO₂Pr O 2,4-diClPh 387 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr O 2,4-diClPh 388 CH₂CH═CHCH₃ Me CH₂OCO₂Bu O Ph 389 CH₂(2-MePr^(c)) Me CH₂OCO₂Bu O Ph 390 CH₂CH═CHCH₃ Me CH₂OCO₂Bu O 2-FPh 391 CH₂(2-MePr^(c)) Me CH₂OCO₂Bu O 2-FPh 392 CH₂CH═CHCH₃ Me CH₂OCO₂Bu O 4-FPh 393 CH₂Pr^(c) Me CH₂OCO₂Bu O 4-FPh 394 CH₂(2-MePr^(c)) Me CH₂OCO₂Bu O 4-FPh 395 CH₂Pn^(c) Me CH₂OCO₂Bu O 4-FPh 396 CH₂Hx^(c) Me CH₂OCO₂Bu O 4-FPh 397 CH₂CH═CHCH₃ Me CH₂OCO₂Bu O 2,4-diFPh 398 CH₂(2-MePr^(c)) Me CH₂OCO₂Bu O 2,4-diFPh 399 CH₂CH═CHCH₃ Me CH₂OCO₂Bu O 2-ClPh 400 CH₂(2-MePr^(c)) Me CH₂OCO₂Bu O 2-ClPh 401 CH₂CH═CHCH₃ Me CH₂OCO₂Bu O 4-ClPh 402 CH₂(2-MePr^(c)) Me CH₂OCO₂Bu O 4-ClPh 403 CH₂CH═CHCH₃ Me CH₂OCO₂Bu O 2-F,4-ClPh 404 CH₂(2-MePr^(c)) Me CH₂OCO₂Bu O 2-F,4-ClPh 405 CH₂CH═CHCH₃ Me CH₂OCO₂Bu O 2-Cl,4-FPh 406 CH₂(2-MePr^(c)) Me CH₂OCO₂Bu O 2-Cl,4-FPh 407 CH₂CH═CHCH₃ Me CH₂OCO₂Bu O 2,4-diClPh 408 CH₂(2-MePr^(c)) Me CH₂OCO₂Bu O 2,4-diClPh 409 CH₂CH═CHCH₃ Me CHO O Ph 410 CH₂Pr^(c) Me CHO O Ph 411 CH₂(2-MePr^(c)) Me CHO O Ph 412 CH₂CH═CHCH₃ Me CHO O 2-FPh 413 CH₂Pr^(c) Me CHO O 2-FPh 414 CH₂(2-MePr^(c)) Me CHO O 2-FPh 415 CH═CHCH₃ Me CHO O 4-FPh 416 CH₂CH═CH₂ Me CHO O 4-FPh 417 CH₂CH═CHCH₃ Me CHO O 4-FPh 418 Pr^(c) Me CHO O 4-FPh 419 2-MePr^(c) Me CHO O 4-FPh 420 CH₂Pr^(c) Me CHO O 4-FPh 421 CR2(2-MePr^(c)) Me CHO O 4-FPh 422 CH₂Bu^(c) Me CHO O 4-FPh 423 CH₂Pn^(c) Me CHO O 4-FPh 424 CH₂Hx^(c) Me CHO O 4-FPh 425 CH₂CH═CHCH₃ Me CHO O 2,4-diFPh 426 CH₂Pr^(c) Me CHO O 2,4-diFPh 427 CH₂(2-MePr^(c)) Me CHO O 2,4-diFPh 428 CH₂CH═CHCH₃ Me CHO O 2-ClPh 429 CH₂Pr^(c) Me CHO O 2-ClPh 430 CH₂(2-MePr^(c)) Me CHO O 2-ClPh 431 CH₂CH═CHCH₃ Me CHO O 4-ClPh 432 CH₂Pr^(c) Me CHO O 4-ClPh 433 CH₂(2-MePr^(c)) Me CHO O 4-ClPh 434 CH₂CH═CHCH₃ Me CHO O 2-F,4-ClPh 435 CH₂Pr^(c) Me CHO O 2-F,4-ClPh 436 CH₂(2-MePr^(c)) Me CHO O 2-F,4-ClPh 437 CH₂CH═CHCH₃ Me CHO O 2-Cl,4-FPh 438 CH₂Pr^(c) Me CHO O 2-Cl,4-FPh 439 CH₂(2-MePr^(c)) Me CHO O 2-Cl,4-FPh 440 CH₂CH═CHCH₃ Me CHO O 2,4-diClPh 441 CH₂Pr^(c) Me CHO O 2,4-diClPh 442 CH₂(2-MePr^(c)) Me CHO O 2,4-diClPh 443 CH₂CH═CHCH₃ Me CO₂H O Ph 444 CH₂Pr^(c) Me CO₂H O Ph 445 CH₂(2-MePr^(c)) Me CO₂H O Ph 446 CH₂CH═CH₂ Me CO₂H O 2-FPh 447 CH₂Pr^(c) Me CO₂H O 2-FPh 448 CH₂(2-MePr^(c)) Me CO₂H O 2-FPh 449 CH═CHCH₃ Me CO₂H O 4-FPh 450 CH₂CH═CH₂ Me CO₂H O 4-FPh 451 CH₂CH═CHCH₃ Me CO₂H O 4-FPh 452 Pr^(c) Me CO₂H O 4-FPh 453 2-MePr^(c) Me CO₂H O 4-FPh 454 CH₂Pr^(c) Me CO₂H O 4-FPh 455 CH₂(2-MePr^(c)) Me CO₂H O 4-FPh 456 CH₂Bu^(c) Me CO₂H O 4-FPh 457 CH₂Pn^(c) Me CO₂H O 4-FPh 458 CH₂Hx^(c) Me CO₂H O 4-FPh 459 CH₂CH═CHCH₃ Me CO₂H O 2,4-diFPh 460 CH₂Pr^(c) Me CO₂H O 2,4-diFPh 461 CH₂(2-MePr^(c)) Me CO₂H O 2,4-diFPh 462 CH₂CH═CHCH₃ Me CO₂H O 2-ClPh 463 CH₂Pr^(c) Me CO₂H O 2-ClPh 464 CH₂(2-MePr^(c)) Me CO₂H O 2-ClPh 465 CH₂CH═CHCH₃ Me CO₂H O 4-ClPh 466 CH₂Pr^(c) Me CO₂H O 4-ClPh 467 CH₂(2-MePr^(c)) Me CO₂H O 4-ClPh 468 CH₂CH═CHCH₃ Me CO₂H O 2-F,4-ClPh 469 CH₂Pr^(c) Me CO₂H O 2-F,4-ClPh 470 CH₂(2-MePr^(c)) Me CO₂H O 2-F,4-ClPh 471 CH₂CH═CHCH₃ Me CO₂H O 2-Cl,4-FPh 472 CH₂Pr^(c) Me CO₂H O 2-Cl,4-FPh 473 CH₂(2-MePr^(c)) Me CO₂H O 2-Cl,4-FPh 474 CH₂CH═CHCH₃ Me CO₂H O 2,4-diClPh 475 CH₂Pr^(c) Me CO₂H O 2,4-diClPh 476 CH₂(2-MePr^(c)) Me CO₂H O 2,4-diClPh 477 CH₂CH═CHCH₃ Me CO₂Me O Ph 478 CH₂(2-MePr^(c)) Me CO₂Me O Ph 479 CH₂CH═CHCH₃ Me CO₂Me O 2-FPh 480 CH₂(2-MePr^(c)) Me CO₂Me O 2-FPh 481 CH═CHCH₃ Me CO₂Me O 4-FPh 482 CH₂CH═CH₂ Me CO₂Me O 4-FPh 483 CH₂CH═CHCH₃ Me CO₂Me O 4-FPh 484 CH₂Pr^(c) Me CO₂Me O 4-FPh 485 CH₂(2-MePr^(c)) Me CO₂Me O 4-FPh 486 CH₂CH═CHCH₃ Me CO₂Me O 2,4-diFPh 487 CH₂Pr^(c) Me CO₂Me O 2,4-diFPh 488 CH₂(2-MePr^(c)) Me CO₂Me O 2,4-diFPh 489 CH₂CH═CHCH₃ Me CO₂Me O 2-ClPh 490 CH₂(2-MePr^(c)) Me CO₂Me O 2-ClPh 491 CH₂CH═CHCH₃ Me CO₂Me O 4-ClPh 492 CH₂(2-MePr^(c)) Me CO₂Me O 4-ClPh 493 CH₂CH═CHCH₃ Me CO₂Me O 2-F,4-ClPh 494 CH₂(2-MePr^(c)) Me CO₂Me O 2-F,4-ClPh 495 CH₂CH═CHCH₃ Me CO₂Me O 2-Cl,4-FPh 496 CH₂(2-MePr^(c)) Me CO₂Me O 2-Cl,4-FPh 497 CH₂CH═CHCH₃ Me CO₂Me O 2,4-diClPh 498 CH₂(2-MePr^(c)) Me CO₂Me O 2,4-dIClPh 499 CH₂CH═CHCH₃ Me CO₂Et O Ph 500 CH₂(2-MePr^(c)) Me CO₂Et O Ph 501 CH₂CH═CHCH₃ Me CO₂Et O 2-FPh 502 CH₂(2-MePr^(c)) Me CO₂Et O 2-FPh 503 CH₂CH═CH₂ Me CO₂Et O 4-FPh 504 CH₂CH═CHCH₃ Me CO₂Et O 4-FPh 505 CH₂Pr^(c) Me CO₂Et O 4-FPh 506 CH₂(2-MePr^(c)) Me CO₂Et O 4-FPh 507 CH₂CH═CHCH₃ Me CO₂Et O 2,4-diFPh 508 CH₂(2-MePr^(c)) Me CO₂Et O 2,4-diFPh 509 CH₂CH═CHCH₃ Me CO₂Et O 2-ClPh 510 CH₂(2-MePr^(c)) Me CO₂Et O 2-ClPh 511 CH₂CH═CHCH₃ Me CO₂Et O 4-ClPh 512 CH₂(2-MePr^(c)) Me CO₂Et O 4-ClPh 513 CH₂CH═CHCH₃ Me CO₂Et O 2-F,4-ClPh 514 CH₂(2-MePr^(c)) Me CO₂Et O 2-F,4-ClPh 515 CH₂CH═CHCH₃ Me CO₂Et O 2-Cl,4-FPh 516 CH₂(2-MePr^(c)) Me CO₂Et O 2-Cl,4-FPh 517 CH₂CH═CHCH₃ Me CO₂Et O 2,4-diClPh 518 CH₂(2-MePr^(c)) Me CO₂Et O 2,4-diClPh 519 CH₂(2-MePr^(c)) Me CO₂Pr O Ph 520 CH₂(2-MePr^(c)) Me CO₂Bu O Ph 521 CH₂CH═CHCH₃ Me CO₂Pr O 2-FPh 522 CH₂CH═CHCH₃ Me CO₂Bu O 2-FPh 523 CH₂CH═CHCH₃ Me CO₂Ph O 2-FPh 524 CH₂(2-MePr^(c)) Me CO₂Pr O 2-FPh 525 CH₂(2-MePr^(c)) Me CO₂Bu O 2-FPh 526 CH₂(2-MePr^(c)) Me CO₂Ph O 2-FPh 527 CH₂(2-MePr^(c)) Me CO₂(4-Me)Ph O 2-FPh 528 CH₂CH═CH₂ Me CO₂Pr O 4-FPh 529 CH₂CH═CH₂ Me CO₂Bu O 4-FPh 530 CH₂CH═CH₂ Me CO₂Ph O 4-FPh 531 CH₂CH═CH₂ Me CO₂(4-Me)Ph O 4-FPh 532 CH₂CH═CHCH₃ Me CO₂Pr O 4-FPh 533 CH₂CH═CHCH₃ Me CO₂Bu O 4-FPh 534 CH₂CH═CHCH₃ Me CO₂Ph O 4-FPh 535 CH₂Pr^(c) Me CO₂Pr O 4-FPh 536 CH₂Pr^(c) Me CO₂Bu O 4-FPh 537 CH₂Pr^(c) Me CO₂Ph O 4-FPh 538 CH₂Pr^(c) Me CO₂(4-Me)Ph O 4-FPh 539 CH₂(2-MePr^(c)) Me CO₂Pr O 4-FPh 540 CH₂(2-MePr^(c)) Me CO₂Bu O 4-FPh 541 CH₂(2-MePr^(c)) Me CO₂Ph O 4-FPh 542 CH₂(2-MePr^(c)) Me CO₂(4-Me)Ph O 4-FPh 543 CH₂(2-MePr^(c)) Me CO₂(4-MeO)Ph O 4-FPh 544 CH₂(2-MePr^(c)) Me CO₂(4-F)Ph O 4-FPh 545 CH₂(2-MePr^(c)) Me CO₂(4-Cl)Ph O 4-FPh 546 CH₂CH═CHCH₃ Me CO₂Pr O 2,4-diFPh 547 CH₂CH═CHCH₃ Me CO₂Bu O 2,4-diFPh 548 CH₂(2-MePr^(c)) Me CO₂Pr O 2,4-diFPh 549 CH₂(2-MePr^(c)) Me CO₂Bu O 2,4-diFPh 550 CH₂(2-MePr^(c)) Me CO₂Ph O 2,4-diFPh 551 CH₂CH═CHCH₃ Me CO₂Pr O 2-ClPh 552 CH₂CH═CHCH₃ Me CO₂Bu O 2-ClPh 553 CH₂(2-MePr^(c)) Me CO₂Pr O 2-ClPh 554 CH₂(2-MePr^(c)) Me CO₂Bu O 2-ClPh 555 CH₂(2-MePr^(c)) Me CO₂Ph O 2-ClPh 556 CH₂CH═CHCH₃ Me CO₂Pr O 4-ClPh 557 CH₂CH═CHCH₃ Me CO₂Bu O 4-ClPh 558 CH₂(2-MePr^(c)) Me CO₂Pr O 4-ClPh 559 CH₂(2-MePr^(c)) Me CO₂Bu O 4-ClPh 560 CH₂(2-MePr^(c)) Me CO₂Ph O 4-ClPh 561 CH₂CH═CHCH₃ Me CO₂Pr O 2-F,4-ClPh 562 CH₂(2-MePr^(c)) Me CO₂Pr O 2-F,4-ClPh 563 CH₂CH═CH₂ Me CO₂Pr O 2-Cl,4-FPh 564 CH₂(2-MePr^(c)) Me CO₂Pr O 2-Cl,4-FPh 565 CH₂CH═CH₂ Me CO₂Pr O 2,4-diClPh 566 CH₂(2-MePr^(c)) Me CO₂Pr O 2,4-diClPh 567 CH₂CH═CH₂ Et CH₂OH O Ph 568 CH₂CH═CH₂ Pr CH₂OH O Ph 569 CH₂Pr^(c) Et CH₂OH O Ph 570 CH₂Pr^(c) Pr CH₂OH O Ph 571 CH₂(2-MePr^(c)) Et CH₂OH O Ph 572 CH₂(2-MePr^(c)) Pr CH₂OH O Ph 573 CH═CHCH₃ Et CH₂OH O 2-FPh 574 CH₂CH═CH₂ Et CH₂OH O 2-FPh 575 CH₂CH═CH₂ Pr CH₂OH O 2-FPh 576 CH₂CH═CHCH₃ Et CH₂OH O 2-FPh 577 CH₂Pr^(c) Et CH₂OH O 2-FPh 578 CH₂Pr^(c) Pr CH₂OH O 2-FPh 579 CH₂(2-MePr^(c)) Et CH₂OH O 2-FPh 580 CIH₂(2-MePr^(c)) Pr CH₂OH O 2-FPh 581 CH₂(2-MePr^(c)) Bu CH₂OH O 2-FPh 582 CH═CH₂ Et CH₂OH O 4-FPh 583 CH═CHCH₃ Et CH₂OH O 4-FPh 584 CH═CHCH₃ Pr CH₂OH O 4-FPh 585 CH₂CH═CH₂ Et CH₂OH O 4-FPh 586 CH₂CH═CH₂ Pr CH₂OH O 4-FPh 587 CH₂CH═CH₂ Bu CH₂OH O 4-FPh 588 CH₂C(CH₃)═CH₂ Et CH₂OH O 4-FPh 589 CH₂CH═CHCH₃ Et CH₂OH O 4-FPh 590 CH₂CH═CHCH₃ Pr CH₂OH O 4-FPh 591 CH₂CH═CF₂ Et CH₂OH O 4-FPh 592 CH₂Pr^(c) Et CH₂OH O 4-FPh 593 CH₂Pr^(c) Pr CH₂OH O 4-FPh 594 CH₂(2-MePr^(c)) Et CH₂OH O 4-FPh 595 CH₂(2-MePr^(c)) Pr CH₂OH O 4-FPh 596 CH₂(2-MePr^(c)) Bu CH₂OH O 4-FPh 597 CH₂Pn^(c) Et CH₂OH O 4-FPh 598 CH₂Hx^(c) Et CH₂OH O 4-FPh 599 CH═CHCH₃ Et CH₂OH O 2,4-diFPh 600 CH₂CH═CH₂ Et CH₂OH O 2,4-diFPh 601 CH₂CH═CH₂ Pr CH₂OH O 2,4-diFPh 602 CH₂CH═CHCH₃ Et CH₂OH O 2,4-diFPh 603 CH₂CH═CF₂ Et CH₂OH O 2,4-diFPh 604 CH₂Pr^(c) Et CH₂OH O 2,4-diFPh 605 CH₂Pr^(c) Pr CH₂OH O 2,4-diFPh 606 CH₂(2-MePr^(c)) Et CH₂OH O 2,4-diFPh 607 CH₂(2-MePr^(c)) Pr CH₂OH O 2,4-diFPh 608 CH₂(2-MePr^(c)) Bu CH₂OH O 2,4-diFPh 609 CH₂CH═CH₂ Et CH₂OAc O Ph 610 CH₂Pr^(c) Et CH₂OAc O Ph 611 CH₂(2-MePr^(c)) Et CH₂OAc O Ph 612 CH₂(2-MePr^(c)) Pr CH₂OAc O Ph 613 CH₂CH═CH₂ Et CH₂OAc O 2-FPh 614 CH₂Pr^(c) Et CH₂OAc O 2-FPh 615 CH₂(2-MePr^(c)) Et CH₂OAc O 2-FPh 616 CH₂(2-MePr^(c)) Pr CH₂OAc O 2-FPh 617 CH═CH₂ Et CH₂OAc O 4-FPh 618 CH═CHCH₃ Et CH₂OAc O 4-FPh 619 CH₂CH═CH₂ Et CH₂OAc O 4-FPh 620 CH₂CH═CH₂ Pr CH₂OAc O 4-FPh 621 CH₂CH═CHCH₃ Et CH₂OAc O 4-FPh 622 CH₂CH═CF₂ Et CH₂OAc O 4-FPh 623 CH₂Pr^(c) Et CH₂OAc O 4-FPh 624 CH₂Pr^(c) Pr CH₂OAc O 4-FPh 625 CH₂(2-MePr^(c)) Et CH₂OAc O 4-FPh 626 CH₂(2-MePr^(c)) Pr CH₂OAc O 4-FPh 627 CH₂(2-MePr^(c)) Bu CH₂OAc O 4-FPh 628 CH₂CH═CH₂ Et CH₂OAc O 2,4-diFPh 629 CH₂CH═CHCH₃ Et CH₂OAc O 2,4-diFPh 630 CH₂CH═CF₂ Et CH₂OAc O 2,4-diFPh 631 CH₂Pr^(c) Et CH₂OAc O 2,4-diFPh 632 CH₂Pr^(c) Pr CH₂OAc O 2,4-diFPh 633 CH₂(2-MePr^(c)) Et CH₂OAc O 2,4-diFPh 634 CH₂(2-MePr^(c)) Pr CH₂OAc O 2,4-diFPh 635 CH₂CH═CH₂ Et CHO O Ph 636 CH₂CH═CH₂ Et CO₂H O Ph 637 CH₂Pr^(c) Et CHO O Ph 638 CH₂Pr^(c) Et CO₂H O Ph 639 CH₂(2-MePr^(c)) Et CHO O Ph 640 CH₂(2-MePr^(c)) Et CO₂H O Ph 641 CH₂CH═CH₂ Et CHO O 2-FPh 642 CH₂CH═CH₂ Et CO₂H O 2-FPh 643 CH₂Pr^(c) Et CHO O 2-FPh 644 CH₂Pr^(c) Et CO₂H O 2-FPh 645 CH₂(2-MePr^(c)) Et CHO O 2-FPh 646 CH₂(2-MePr^(c)) Et CO₂H O 2-FPh 647 CH═CHCH₃ Et CHO O 4-FPh 648 CH═CHCH₃ Et CO₂H O 4-FPh 649 CH₂CH═CH₂ Et CHO O 4-FPh 650 CH₂CH═CH₂ Et CO₂H O 4-FPh 651 CH₂CH═CH₂ Et CO₂Me O 4-FPh 652 CH₂CH═CH₂ Et CO₂Et O 4-FPh 653 CH₂CH═CH₂ Pr CHO O 4-FPh 654 CH₂CH═CH₂ Pr CO₂H O 4-FPh 655 CH₂CH═CHCH₃ Et CHO O 4-FPh 656 CH₂CH═CHCH₃ Et CO₂H O 4-FPh 657 CH₂CH═CF₂ Et CHO O 4-FPh 658 CH₂CH═CF₂ Et CO₂H O 4-FPh 659 CH₂Pr^(c) Et CHO O 4-FPh 660 CH₂Pr^(c) Et CO₂H O 4-FPh 661 CH₂Pr^(c) Et CO₂Me O 4-FPh 662 CH₂Pr^(c) Et CO₂Et O 4-FPh 663 CH₂Pr^(c) Pr CHO O 4-FPh 664 CH₂Pr^(c) Pr CO₂H O 4-FPh 665 CH₂(2-MePr^(c)) Et CHO O 4-FPh 666 CH₂(2-MePr^(c)) Et CO₂H O 4-FPh 667 CH₂(2-MePr^(c)) Et CO₂Me O 4-FPh 668 CH₂(2-MePr^(c)) Et CO₂Et O 4-FPh 669 CH₂(2-MePr^(c)) Pr CHO O 4-FPh 670 CH₂(2-MePr^(c)) Pr CO₂H O 4-FPh 671 CH₂(2-MePr^(c)) Bu CHO O 4-FPh 672 CH₂(2-MePr^(c)) Bu CO₂H O 4-FPh 673 CH₂CH═CH₂ Et CHO O 2,4-diFPh 674 CH₂CH═CH₂ Et CO₂H O 2,4-diFPh 675 CH₂CH═CHCH₃ Et CHO O 2,4-diFPh 676 CH₂CH═CHCH₃ Et CO₂H O 2,4-diFPh 677 CH₂CH═CF₂ Et CHO O 2,4-diFPh 678 CH₂CH═CF₂ Et CO₂H O 2,4-diFPh 679 CH₂Pr^(c) Et CHO O 2,4-diFPh 680 CH₂Pr^(c) Et CO₂H O 2,4-diFPh 681 CH₂(2-MePr^(c)) Et CHO O 2,4-diFPh 682 CH₂(2-MePr^(c)) Et CO₂H O 2,4-diFPh 683 CH₂(2-MePr^(c)) Et CO₂Me O 2,4-diFPh 684 CH₂(2-MePr^(c)) Et CO₂Et O 2,4-diFPh 685 CH₂(2-MePr^(c)) Pr CHO O 2,4-diFPh 686 CH₂(2-MePr^(c)) Pr CO₂H O 2,4-diFPh 687 CH₂CH═CH₂ Me CH₂OH O 4-MePh 688 CH₂CH═CH₂ Me CH₂OH O 4-CF₃Ph 689 CH₂CH═CH₂ Me CH₂OH O 4-MeOPh 690 CH₂CH═CH₂ Me CH₂OH O 4-CHF₂OPh 691 CH₂CH═CH₂ Me CH₂OH O 4-CF₃OPh 692 CH₂CH═CH₂ Me CH₂OH O 4-BrPh 693 CH₂CH═CHCH₃ Me CH₂OH O 4-CF₃Ph 694 CH₂CH═CHCH₃ Me CH₂OH O 4-CHF₂OPh 695 CH₂CH═CHCH₃ Me CH₂OH O 4-CF₃OPh 696 CH₂Pr^(c) Me CH₂OH O 4-MePh 697 CH₂Pr^(c) Me CH₂OH O 4-CF₃Ph 698 CH₂Pr^(c) Me CH₂OH O 4-MeOPh 699 CH₂Pr^(c) Me CH₂OH O 4-CHF₂OPh 700 CH₂Pr^(c) Me CH₂OH O 4-CF₃OPh 701 CH₂Pr^(c) Me CH₂OH O 4-BrPh 7O2 CH₂(2-MePr^(c)) Me CH₂OH O 4-MePh 703 CH₂(2-MePr^(c)) Me CH₂OH O 4-CF₃Ph 704 CH₂(2-MePr^(c)) Me CH₂OH O 4-MeOPh 705 CH₂(2-MePr^(c)) Me CH₂OH O 4-CHF₂OPh 706 CH₂(2-MePr^(c)) Me CH₂OH O 4-CF₃OPh 707 CH₂(2-MePr^(c)) Me CH₂OH O 4-BrPh 708 CH₂CH═CH₂ Me CH₂OAc O 4-MePh 709 CH₂CH═CH₂ Me CH₂OAc O 4-CF₃Ph 710 CH₂CH═CH₂ Me CH₂OAc O 4-MeOPh 711 CH₂CH═CH₂ Me CH₂OAc O 4-CHF₂OPh 712 CH₂CH═CH₂ Me CH₂OAc O 4-CF₃OPh 713 CH₂CH═CH₂ Me CH₂OAc O 4-BrPh 714 CH₂CH═CHCH₃ Me CH₂OAc O 4-CF₃Ph 715 CH₂CH═CHCH₃ Me CH₂OAc O 4-CHF₂OPh 716 CH₂CH═CHCH₃ Me CH₂OAc O 4-CF₃OPh 717 CH₂Pr^(c) Me CH₂OAc O 4-MePh 718 CH₂Pr^(c) Me CH₂OAc O 4-CF₃Ph 719 CH₂Pr^(c) Me CH₂OAc O 4-MeOPh 720 CH₂Pr^(c) Me CH₂OAc O 4-CHF₂OPh 721 CH₂Pr^(c) Me CH₂OAc O 4-CF₃OPh 722 CH₂Pr^(c) Me CH₂OAc O 4-BrPh 723 CH₂(2-MePr^(c)) Me CH₂OAc O 4-MePh 724 CH₂(2-MePr^(c)) Me CH₂OAc O 4-CF₃Ph 725 CH₂(2-MePr^(c)) Me CH₂OAc O 4-MeOPh 726 CH₂(2-MePr^(c)) Me CH₂OAc O 4-CHF₂OPh 727 CH₂(2-MePr^(c)) Me CH₂OAc O 4-CF₃OPh 728 CH₂(2-MePr^(c)) Me CH₂OAc O 4-BrPh 729 CH₂CH═CH₂ Me CH₂OPrp O 4-CF₃Ph 730 CH₂CH═CH₂ Me CH₂OBur O 4-CF₃Ph 731 CH₂CH═CH₂ Me CH₂OCO₂Me O 4-CF₃Ph 732 CH₂CH═CH₂ Me CH₂OCO₂Et O 4-CF₃Ph 733 CH₂CH═CH₂ Me CHO O 4-CF₃Ph 734 CH₂CH═CH₂ Me CO₂H O 4-CF₃Ph 735 CH₂CH═CH₂ Me CO₂Me O 4-CF₃Ph 736 CH₂CH═CH₂ Me CO₂Et O 4-CF₃Ph 737 CH₂CH═CH₂ Me CH₂OPrp O 4-CF₃OPh 738 CH₂CH═CH₂ Me CH₂OBur O 4-CF₃OPh 739 CH₂CH═CH₂ Me CH₂OCO₂Me O 4-CF₃OPh 740 CH₂CH═CH₂ Me CH₂OCO₂Et O 4-CF₃OPh 741 CH₂CH═CH₂ Me CHO O 4-CF₃OPh 742 CH₂CH═CH₂ Me CO₂H O 4-CF₃OPh 743 CH₂CH═CH₂ Me CO₂Me O 4-CF₃OPh 744 CH₂CH═CH₂ Me CO₂Et O 4-CF₃OPh 745 CH₂Pr^(c) Me CH₂OPrp O 4-CF₃Ph 746 CH₂Pr^(c) Me CH₂OBur O 4-CF₃Ph 747 CH₂Pr^(c) Me CH₂OCO₂Me O 4-CF₃Ph 748 CH₂Pr^(c) Me CH₂OCO₂Et O 4-CF₃Ph 749 CH₂Pr^(c) Me CHO O 4-CF₃Ph 750 CH₂Pr^(c) Me CO₂H O 4-CF₃Ph 751 CH₂Pr^(c) Me CO₂Me O 4-CF₃Ph 752 CH₂Pr^(c) Me CO₂Et O 4-CF₃Ph 753 CH₂Pr^(c) Me CH₂OPrp O 4-CF₃OPh 754 CH₂Pr^(c) Me CH₂OBur O 4-CF₃OPh 755 CH₂Pr^(c) Me CH₂OCO₂Me O 4-CF₃OPh 756 CH₂Pr^(c) Me CH₂OCO₂Et O 4-CF₃OPh 757 CH₂Pr^(c) Me CHO O 4-CF₃OPh 758 CH₂Pr^(c) Me CO₂H O 4-CF₃OPh 759 CH₂Pr^(c) Me CO₂Me O 4-CF₃OPh 760 CH₂Pr^(c) Me CO₂Et O 4-CF₃OPh 761 CH₂(2-MePr^(c)) Me CH₂OPrp O 4-MePh 762 CH₂(2-MePr^(c)) Me CH₂OBur O 4-MePh 763 CH₂(2-MePr^(c)) Me CH₂OCO₂Me O 4-MePh 764 CH₂(2-MePr^(c)) Me CH₂OCO₂Et O 4-MePh 765 CH₂(2-MePr^(c)) Me CHO O 4-MePh 766 CH₂(2-MePr^(c)) Me CO₂H O 4-MePh 767 CH₂(2-MePr^(c)) Me CH₂OPrp O 4-CF₃Ph 768 CH₂(2-MePr^(c)) Me CH₂OBur O 4-CF₃Ph 769 CH₂(2-MePr^(c)) Me CH₂OCOPh O 4-CF₃Ph 77O CH₂(2-MePr^(c)) Me CH₂OCO₂Me O 4-CF₃Ph 771 CH₂(2-MePr^(c)) Me CH₂OCO₂Et O 4-CF₃Ph 772 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr O 4-CF₃Ph 773 CH₂(2-MePr^(c)) Me CHO O 4-CF₃Ph 774 CH₂(2-MePr^(c)) Me CO₂H O 4-CF₃Ph 775 CH₂(2-MePr^(c)) Me CO₂Me O 4-CF₃Ph 776 CH₂(2-MePr^(c)) Me CO₂Et O 4-CF₃Ph 777 CH₂(2-MePr^(c)) Me CO₂Ph O 4-CF₃Ph 778 CH₂(2-MePr^(c)) Me CH₂OPrp O 4-MeOPh 779 CH₂(2-MePr^(c)) Me CH₂OBur O 4-MeOPh 78O CH₂(2-MePr^(c)) Me CH₂OCO₂Me O 4-MeOPh 781 CH₂(2-MePr^(c)) Me CH₂OCO₂Et O 4-MeOPh 782 CH₂(2-MePr^(c)) Me CHO O 4-MeOPh 783 CH₂(2-MePr^(c)) Me CO₂H O 4-MeOPh 784 CH₂(2-MePr^(c)) Me CH₂OPrp O 4-CHF₂OPh 785 CH₂(2-MePr^(c)) Me CH₂OBur O 4-CHF₂OPh 786 CH₂(2-MePr^(c)) Me CH₂OCO₂Me O 4-CHF₂OPh 787 CH₂(2-MePr^(c)) Me CH₂OCO₂Et O 4-CHF₂OPh 788 CH₂(2.MePr^(c)) Me CHO O 4-CHF₂OPh 789 CH₂(2.MePr^(c)) Me CO₂H O 4-CHF₂OPh 790 CH₂(2-MePr^(c)) Me CH₂OPrp O 4-CF₃OPh 791 CH₂(2-MePr^(c)) Me CH₂OBur O 4-CF₃OPh 792 CH₂(2-MePr^(c)) Me CH₂OCOPh O 4-CF₃OPh 793 CH₂(2-MePr^(c)) Me CH₂OCO₂Me O 4-CF₃OPh 794 CH₂(2-MePr^(c)) Me CH₂OCO₂Et O 4-CF₃OPh 795 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr O 4-CF₃OPh 796 CH₂(2-MePr^(c)) Me CHO O 4-CF₃OPh 797 CH₂(2-MePr^(c)) Me CO₂H O 4-CF₃OPh 798 CH₂(2-MePr^(c)) Me CO₂Me O 4-CF₃OPh 799 CH₂(2-MePr^(c)) Me CO₂Et O 4-CF₃OPh 800 CH₂(2-MePr^(c)) Me CO₂Ph O 4-CF₃OPh 801 CH₂(2-MePr^(c)) Me CH₂OPrp O 4-BrPh 8O2 CH₂(2-MePr^(c)) Me CH₂OBur O 4-BrPh 803 CH₂(2-MePr^(c)) Me CH₂OCO₂Me O 4-BrPh 804 CH₂(2-MePr^(c)) Me CH₂OCO₂Et O 4-BrPh 805 CH₂(2-MePr^(c)) Me CHO O 4-BrPh 806 CH₂(2-MePr^(c)) Me CO₂H O 4-BrPh 807 CH₂CH═CH₂ Me CH₂OH S Ph 808 CH₂CH═CH₂ Me CH₂OH NH Ph 809 CH₂CH═CHCH₃ Me CH₂OH S Ph 810 CH₂Pr^(c) Me CH₂OH S Ph 811 CH₂Pr^(c) Me CH₂OH NH Ph 812 CH₂(2-MePr^(c)) Me CH₂OH S Ph 813 CH₂(2-MePr^(c)) Me CH₂OH NH Ph 814 CH₂CH═CH₂ Me CH₂OH S 2-FPh 815 CH₂CH═CH₂ Me CH₂OH NH 2-FPh 816 CH₂CH═CHCH₃ Me CH₂OH S 2-FPh 817 CH₂Pr^(c) Me CH₂OH S 2-FPh 818 CH₂Pr^(c) Me CH₂OH NH 2-FPh 819 CH₂(2-MePr^(c)) Me CH₂OH S 2-FPh 820 CH₂(2-MePr^(c)) Me CH₂OH NH 2-FPh 821 CH═CHCH₃ Me CH₂OH S 4-FPh 822 CH₂CH═CH₂ Me CH₂OH S 4-FPh 823 CH₂CH═CH₂ Me CH₂OH NH 4-FPh 824 CH₂C(CH₃)═CH₂ Me CH₂OH S 4-FPh 825 CH₂CH═CHCH₃ Me CH₂OH S 4-FPh 826 CH₂CH═CHCH₃ Me CH₂OH NH 4-FPh 827 CH₂CH═CF₂ Me CH₂OH S 4-FPh 828 CH₂CH═CHCl Me CH₂OH S 4-FPh 829 CH₂CCl₂ Me CH₂OH S 4-FPh 830 Pr^(c) Me CH₂OH S 4-FPh 831 2-MePr^(c) Me CH₂OH S 4-FPh 832 CH₂Pr^(c) Me CH₂OH S 4-FPh 833 CH₂Pr^(c) Me CH₂OH NH 4-FPh 834 CH₂(2-MePr^(c)) Me CH₂OH S 4-FPh 835 CH₂(2-MePr^(c)) Me CH₂OH NH 4-FPh 836 CH₂Bu^(c) Me CH₂OH S 4-FPh 837 CH₂Pn^(c) Me CH₂OH S 4-FPh 838 CH₂(2-MePn^(c)) Me CH₂OH S 4-FPh 839 CH₂Hx^(c) Me CH₂OH S 4-FPh 840 CH₂(2-MeHx^(c)) Me CH₂OH S 4-FPh 841 CH₂CH═CH₂ Me CH₂OH S 2,4-diFPh 842 CH₂CH═CH₂ Me CH₂OH NH 2,4-diFPh 843 CH₂CH═CHCH₃ Me CH₂OH S 2,4-diFPh 844 CH₂CH═CHCH₃ Me CH₂OH NH 2,4-diFPh 845 CH₂Pr^(c) Me CH₂OH S 2,4-diFPh 846 CH₂(2-MePr^(c)) Me CH₂OH S 2,4-diFPh 847 CH₂(2-MePr^(c)) Me CH₂OH NH 2,4-diFPh 848 CH₂Bu^(c) Me CH₂OH S 2,4-diFPh 849 CH₂Pn^(c) Me CH₂OH S 2,4-diFPh 850 CH₂Hx^(c) Me CH₂OH S 2,4-diFPh 851 CH₂CH═CH₂ Me CH₂OH S 2-ClPh 852 CH₂Pr^(c) Me CH₂OH S 2-ClPh 853 CH₂(2-MePr^(c)) Me CH₂OH S 2-ClPh 854 CH₂(2-MePr^(c)) Me CH₂OH NH 2-ClPh 855 CH₂CH═CH₂ Me CH₂OH S 4-ClPh 856 CH₂CH═CHCH₃ Me CH₂OH S 4-ClPh 857 CH₂Pr^(c) Me CH₂OH S 4-ClPh 858 CH₂(2-MePr^(c)) Me CH₂OH S 4-ClPh 859 CH₂(2-MePr^(c)) Me CH₂OH NH 4-ClPh 860 CH₂CH═CH₂ Me CH₂OH S 2,4-diClPh 861 CH₂Pr^(c) Me CH₂OH S 2,4-diClPh 862 CH₂(2-MePr^(c)) Me CH₂OH S 2,4-diClPh 863 CH₂CH═CH₂ Me CH₂OAc S Ph 864 CH₂CH═CH₂ Me CH₂OAc NH Ph 865 CH₂CH═CHCH₃ Me CH₂OAc S Ph 866 CH₂Pr^(c) Me CH₂OAc S Ph 867 CH₂(2-MePr^(c)) Me CH₂OAc S Ph 868 CH₂(2-MePr^(c)) Me CH₂OAc NH Ph 869 CH₂CH═CH₂ Me CH₂OAc S 2-FPh 870 CH₂CH═CH₂ Me CH₂OAc NH 2-FPh 871 CH₂CH═CHCH₃ Me CH₂OAc S 2-FPh 872 CH₂Pr^(c) Me CH₂OAc S 2-FPh 873 CH₂(2-MePr^(c)) Me CH₂OAc S 2-FPh 874 CH₂(2-MePr^(c)) Me CH₂OAc NH 2-FPh 875 CH═CH₂ Me CH₂OAc S 4-FPh 876 CH═CHCH₃ Me CH₂OAc S 4-FPh 877 CH₂CH═CH₂ Me CH₂OAc S 4-FPh 878 CH₂CH═CH₂ Me CH₂OAc NH 4-FPh 879 CH₂C(CH₃)═CH₂ Me CH₂OAc S 4-FPh 880 CH₂CH═CHCH₃ Me CH₂OAc S 4-FPh 881 CH₂CH═CHCH₃ Me CH₂OAc NH 4-FPh 882 CH₂CH═CF₂ Me CH₂OAc S 4-FPh 883 CH₂CH═CHCl Me CH₂OAc S 4-FPh 884 CH₂CH═CCl₂ Me CH₂OAc S 4-FPh 885 Pr^(c) Me CH₂OAc S 4-FPh 886 2-MePr^(c) Me CH₂OAc S 4-FPh 887 CH₂Pr^(c) Me CH₂OAc S 4-FPh 888 CH₂Pr^(c) Me CH₂OAc NH 4-FPh 889 CH₂(2-MePr^(c)) Me CH₂OAc S 4-FPh 890 CH₂(2-MePr^(c)) Me CH₂OAc NH 4-FPh 891 CH₂Bu^(c) Me CH₂OAc S 4-FPh 892 CH₂Pn^(c) Me CH₂OAc S 4-FPh 893 CH₂(2-MePn^(c)) Me CH₂OAc S 4-FPh 894 CH₂Hx^(c) Me CH₂OAc S 4-FPh 895 CH₂(2-MeHx^(c)) Me CH₂OAc S 4-FPh 896 CH₂CH═CH₂ Me CH₂OAc S 2,4-diFPh 897 CH₂CH═CH₂ Me CH₂OAc NH 2,4-diFPh 898 CH₂CH═CHCH₃ Me CH₂OAc S 2,4-diFPh 899 CH₂CH═CF₂ Me CH₂OAc S 2,4-diFPh 900 CH₂Pr^(c) Me CH₂OAc S 2,4-diFPh 901 CH₂(2-MePr^(c)) Me CH₂OAc S 2,4-diFPh 902 CH₂(2-MePr^(c)) Me CH₂OAc NH 2,4-diFPh 903 CH₂CH═CH₂ Me CH₂OAc S 2-ClPh 904 CH₂CH═CH₂ Me CH₂OAc NH 2-ClPh 905 CH₂CH═CHCH₃ Me CH₂OAc S 2-ClPh 906 CH₂Pr^(c) Me CH₂OAc S 2-ClPh 907 CH₂(2-MePr^(c)) Me CH₂OAc S 2-ClPh 908 CH₂(2-MePr^(c)) Me CH₂OAc NH 2-ClPh 909 CH₂CH═CH₂ Me CH₂OAc S 4-ClPh 910 CH₂CH═CH₂ Me CH₂OAc NH 4-ClPh 911 CH₂CH═CHCH₃ Me CH₂OAc S 4-ClPh 912 CH₂Pr^(c) Me CH₂OAc S 4-ClPh 913 CH₂(2-MePr^(c)) Me CH₂OAc S 4-ClPh 914 CH₂(2-MePr^(c)) Me CH₂OAc NH 4-ClPh 915 CH₂CH═CH₂ Me CH₂OAc S 2,4-diClPh 916 CH₂Pr^(c) Me CH₂OAc S 2,4-diClPh 917 CH₂(2-MePr^(c)) Me CH₂OAc S 2,4-diClPh 918 CH₂CH═CH₂ Me CH₂OPrp S Ph 919 CH₂Pr^(c) Me CH₂OPrp S Ph 920 CH₂(2-MePr^(c)) Me CH₂OPrp S Ph 921 CH₂(2-MePr^(c)) Me CH₂OPrp NH Ph 922 CH₂CH═CH₂ Me CH₂OPrp S 2-FPh 923 CH₂Pr^(c) Me CH₂OPrp S 2-FPh 924 CH₂(2-MePr^(c)) Me CH₂OPrp S 2-FPh 925 CH₂(2-MePr^(c)) Me CH₂OPrp NH 2-FPh 926 CH₂CH═CH₂ Me CH₂OPrp S 4-FPh 927 CH₂CH═CH₂ Me CH₂OPrp NH 4-FPh 928 CH₂CH═CHCH₃ Me CH₂OPrp S 4-FPh 929 CH₂Pr^(c) Me CH₂OPrp S 4-FPh 930 CH₂(2-MePr^(c)) Me CH₂OPrp S 4-FPh 931 CH₂(2-MePr^(c)) Me CH₂OPrp NH 4-FPh 932 CH₂Bu^(c) Me CH₂OPrp S 4-FPh 933 CH₂Pn^(c) Me CH₂OPrp S 4-FPh 934 CH₂Hx^(c) Me CH₂OPrp S 4-FPh 935 CH₂CH═CH₂ Me CH₂OPrp S 2,4-diFPh 936 CH₂CH═CH₂ Me CH₂OPrp NH 2,4-diFPh 937 CH₂CH═CHCH₃ Me CH₂OPrp S 2,4-diFPh 938 CH₂Pr^(c) Me CH₂OPrp S 2,4-diFPh 939 CH₂(2-MePr^(c)) Me CH₂OPrp S 2,4-diFPh 940 CH₂(2-MePr^(c)) Me CH₂OPrp NH 2,4-diFPh 941 CH₂CH═CH₂ Me CH₂OPrp S 2-ClPh 942 CH₂Pr^(c) Me CH₂OPrp S 2-ClPh 943 CH₂(2-MePr^(c)) Me CH₂OPrp S 2-ClPh 944 CH₂(2-MePr^(c)) Me CH₂OPrp NH 2-ClPh 945 CH₂CH═CH₂ Me CH₂OPrp S 4-ClPh 946 CH₂Pr^(c) Me CH₂OPrp S 4-ClPh 947 CH₂(2-MePr^(c)) Me CH₂OPrp S 4-ClPh 948 CH₂(2-MePr^(c)) Me CH₂OPrp NH 4-ClPh 949 CH₂CH═CH₂ Me CH₂OPrp S 2,4-diClPh 950 CH₂Pr^(c) Me CH₂OPrp S 2,4-diClPh 951 CH₂(2-MePr^(c)) Me CH₂OPrp S 2,4-diClPh 952 CH₂(2-MePr^(c)) Me CH₂OBur S Ph 953 CH₂CH═CH₂ Me CH₂OBur S 2-FPh 954 CH₂Pr^(c) Me CH₂OBur S 2-FPh 955 CH₂(2-MePr^(c)) Me CH₂OBur S 2-FPh 956 CH₂CH═CH₂ Me CH₂OBur S 4-FPh 957 CH₂CH═CH₂ Me CH₂OBur NH 4-FPh 958 CH₂CH═CHCH₃ Me CH₂OBur S 4-FPh 959 Pr^(c) Me CH₂OBur S 4-FPh 960 2-MePr^(c) Me CH₂OBur S 4-FPh 961 CH₂Pr^(c) Me CH₂OBur S 4-FPh 962 CH₂(2-MePr^(c)) Me CH₂OBur S 4-FPh 963 CH₂(2-MePr^(c)) Me CH₂OBur NH 4-FPh 964 CH₂Bu^(c) Me CH₂OBur S 4-FPh 965 CH₂Pn^(c) Me CH₂OBur S 4-FPh 966 CH₂Hx^(c) Me CH₂OBur S 4-FPh 967 CH₂CH═CH₂ Me CH₂OBur S 2,4-diFPh 968 CH₂CH═CH₂ Me CH₂OBur NH 2,4-diFPh 969 CH₂Pr^(c) Me CH₂OBur S 2,4-diFPh 970 CH₂(2-MePr^(c)) Me CH₂OBur S 2,4-diFPh 971 CH₂(2-MePr^(c)) Me CH₂OBur NH 2,4-diFPh 972 CH₂CH═CH₂ Me CH₂OBur S 2-ClPh 973 CH₂Pr^(c) Me CH₂OBur S 2-ClPh 974 CH₂(2-MePr^(c)) Me CH₂OBur S 2-ClPh 975 CH₂(2-MePr^(c)) Me CH₂OBur NH 2-ClPh 976 CH₂CH═CH₂ Me CH₂OBur S 4-ClPh 977 CH₂Pr^(c) Me CH₂OBur S 4-ClPh 978 CH₂(2-MePr^(c)) Me CH₂OBur S 4-ClPh 979 CH₂(2-MePr^(c)) Me CH₂OBur NH 4-ClPh 980 CH₂CH═CH₂ Me CH₂OBur S 2,4-diClPh 981 CH₂Pr^(c) Me CH₂OBur S 2,4-diClPh 982 CH₂(2-MePr^(c)) Me CH₂OBur S 2,4-diClPh 983 CH₂(2-MePr^(c)) Me CH₂OBur NH 2,4-diClPh 984 CH₂(2.MePr^(c)) Me CH₂OCOPh S Ph 985 CH₂CH═CH₂ Me CH₂OCOPh S 2-FPh 986 CH₂(2-MePr^(c)) Me CH₂OCOPh S 2-FPh 987 CH₂CH═CH₂ Me CH₂OCOPh S 4-FPh 988 CH₂CH═CHCH₃ Me CH₂OCOPh S 4-FPh 989 CH₂Pr^(c) Me CH₂OCOPh S 4-FPh 990 CH₂(2-MePr^(c)) Me CH₂OCOPh S 4-FPh 991 CH₂(2-MePr^(c)) Me CH₂OCOPh NH 4-FPh 992 CH₂CH═CH₂ Me CH₂OCOPh S 2,4-diFPh 993 CH₂CH═CHCH₃ Me CH₂OCOPh S 2,4-diFPh 994 CH₂P^(c) Me CH₂OCOPh S 2,4-diFPh 995 CH₂(2-MePr^(c)) Me CH₂OCOPh S 2,4-diFPh 996 CH₂(2-MePr^(c)) Me CH₂OCOPh NH 2,4-diFPh 997 CH₂CH═CH₂ Me CH₂OCOPh S 2-ClPh 998 CH₂(2-MePr^(c)) Me CH₂OCOPh S 2-ClPh 999 CH₂CH═CH₂ Me CH₂OCOPh S 4-ClPh 1000 CH₂Pr^(c) Me CH₂OCOPh S 4-ClPh 1001 CH₂(2-MePr^(c)) Me CH₂OCOPh S 4-ClPh 1002 CH₂(2-MePr^(c)) Me CH₂OCOPh NH 4-ClPh 1003 CH₂CH═CH₂ Me CH₂OCOPh S 2,4-diClPh 1004 CH₂Pr^(c) Me CH₂OCOPh S 2,4-diClPh 1005 CH₂(2-MePr^(c)) Me CH₂OCOPh S 2,4-diClPh 1006 CH₂(2-MePr^(c)) Me CH₂OCOPh NH 2,4-diClPh 1007 CH₂(2-MePr^(c)) Me CH₂OCO₂Me S Ph 1008 CH₂CH═CH₂ Me CH₂OCO₂Me S 2-FPh 1009 CH₂(2-MePr^(c)) Me CH₂OCO₂Me S 2-FPh 1010 CH₂CH═CH₂ Me CH₂OCO₂Me S 4-FPh 1011 CH₂CH═CH₂ Me CH₂OCO₂Me NH 4-FPh 1012 CH₂CH═CHCH₃ Me CH₂OCO₂Me S 4-FPh 1013 CH₂Pr^(c) Me CH₂OCO₂Me S 4-FPh 1014 CH₂(2-MePr^(c)) Me CH₂OCO₂Me S 4-FPh 1015 CH₂(2-MePr^(c)) Me CH₂OCO₂Me NH 4-FPh 1016 CH₂CH═CH₂ Me CH₂OCO₂Me S 2,4-diFPh 1017 CH₂Pr^(c) Me CH₂OCO₂Me S 2,4-diFPh 1018 CH₂(2-MePr^(c)) Me CH₂OCO₂Me S 2,4-diFPh 1019 CH₂(2-MePr^(c)) Me CH₂OCO₂Me NH 2,4-diFPh 1020 CH₂CH═CH₂ Me CH₂OCO₂Me S 2-ClPh 1021 CH₂(2-MePr^(c)) Me CH₂OCO₂Me S 2-ClPh 1022 CH₂CH═CH₂ Me CH₂OCO₂Me S 4-ClPh 1023 CH₂Pr^(c) Me CH₂OCO₂Me S 4-ClPh 1024 CH₂(2-MePr^(c)) Me CH₂OCO₂Me S 4-ClPh 1025 CH₂(2-MePr^(c)) Me CH₂OCO₂Me NH 4-ClPh 1026 CH₂CH═CH₂ Me CH₂OCO₂Me S 2,4-diClPh 1027 CH₂Pr^(c) Me CH₂OCO₂Me S 2,4-diClPh 1028 CH₂(2-MePr^(c)) Me CH₂OCO₂Me S 2,4-diClPh 1029 CH₂(2-MePr^(c)) Me CH₂OCO₂Me NH 2,4-diClPh 1030 CH₂(2-MePr^(c)) Me CH₂OCO₂Et S Ph 1031 CH₂CH═CH₂ Me CH₂OCO₂Et S 2-FPh 1032 CH₂(2-MePr^(c)) Me CH₂OCO₂Et S 2-FPh 1033 CH₂CH═CH₂ Me CH₂OCO₂Et S 4-FPh 1034 CH₂CH═CH₂ Me CH₂OCO₂Et NH 4-FPh 1035 CH₂CH═CHCH₃ Me CH₂OCO₂Et S 4-FPh 1036 CH₂Pr^(c) Me CH₂OCO₂Et S 4-FPh 1037 CH₂(2-MePr^(c)) Me CH₂OCO₂Et S 4-FPh 1038 CH₂(2-MePr^(c)) Me CH₂OCO₂Et NH 4-FPh 1039 CH₂CH═CH₂ Me CH₂OCO₂Et S 2,4-diFPh 1040 CH₂Pr^(c) Me CH₂OCO₂Et S 2,4-diFPh 1041 CH₂(2-MePr^(c)) Me CH₂OCO₂Et S 2,4-diFPh 1042 CH₂(2-MePr^(c)) Me CH₂OCO₂Et NH 2,4-diFPh 1043 CH₂CH═CH₂ Me CH₂OCO₂Et S 2-ClPh 1044 CH₂(2-MePr^(c)) Me CH₂OCO₂Et S 2-ClPh 1045 CH₂CH═CH₂ Me CH₂OCO₂Et S 4-ClPh 1046 CH₂Pr^(c) Me CH₂OCO₂Et S 4-ClPh 1047 CH₂(2-MePr^(c)) Me CH₂OCO₂Et S 4-ClPh 1048 CH₂(2-MePr^(c)) Me CH₂OCO₂Et NH 4-ClPh 1049 CH₂CH═CH₂ Me CH₂OCO₂Et S 2,4-diClPh 1050 CH₂Pr^(c) Me CH₂OCO₂Et S 2,4-diClPh 1051 CH₂(2-MePr^(c)) Me CH₂OCO₂Et S 2,4-diClPh 1052 CH₂(2-MePr^(c)) Me CH₂OCO₂Et NH 2,4-diClPh 1053 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr S Ph 1054 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr S 2-FPh 1055 CH₂CH═CH₂ Me CH₂OCO₂Pr S 4-FPh 1056 CH₂Pr^(c) Me CH₂OCO₂Pr S 4-FPh 1057 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr S 4-FPh 1058 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr NH 4-FPh 1059 CH₂CH═CH₂ Me CH₂OCO₂Pr S 2,4-diFPh 1060 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr S 2,4-diFPh 1061 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr NH 2,4-diFPh 1062 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr S 2-ClPh 1063 CH₂CH═CH₂ Me CH₂OCO₂Pr S 4-ClPh 1064 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr S 4-ClPh 1065 CH₂CH═CH₂ Me CH₂OCO₂Pr S 2,4-diClPh 1066 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr S 2,4-diClPh 1067 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr NH 2,4-diClPh 1068 CH₂(2-MePr^(c)) Me CH₂OCO₂Bu S Ph 1069 CH₂(2-MePr^(c)) Me CH₂OCO₂Bu S 2-FPh 1070 CH₂CH═CH₂ Me CH₂OCO₂Bu S 4-FPh 1071 CH₂Pr^(c) Me CH₂OCO₂Bu S 4-FPh 1072 CH₂(2-MePr^(c)) Me CH₂OCO₂Bu S 4-FPh 1073 CH₂(2-MePr^(c)) Me CH₂OCO₂Bu NH 4-FPh 1074 CH₂CH═CH₂ Me CH₂OCO₂Bu S 2,4-diFPh 1075 CH₂(2-MePr^(c)) Me CH₂OCO₂Bu S 2,4-diFPh 1076 CH₂(2-MePr^(c)) Me CH₂OCO₂Bu NH 2,4-diFPh 1077 CH₂(2-MePr^(c)) Me CH₂OCO₂Bu S 2-ClPh 1078 CH₂CH═CH₂ Me CH₂OCO₂Bu S 4-ClPh 1079 CH₂(2-MePr^(c)) Me CH₂OCO₂Bu S 4-ClPh 1080 CH₂CH═CH₂ Me CH₂OCO₂Bu S 2,4-diClPh 1081 CH₂(2-MePr^(c)) Me CH₂OCO₂Bu S 2,4-diClPh 1082 CH₂(2-MePr^(c)) Me CH₂OCO₂Bu NH 2,4-diClPh 1083 CH₂(2-MePr^(c)) Me CHO S Ph 1084 CH₂CH═CH₂ Me CHO S 2-FPh 1085 CH₂(2-MePr^(c)) Me CHO S 2-FPh 1086 CH₂CH═CH₂ Me CHO S 4-FPh 1087 CH₂CH═CH₂ Me CHO NH 4-FPh 1088 CH₂CHCH═CH₃ Me CHO S 4-FPh 1089 CH₂Pr^(c) Me CHO S 4-FPh 1090 CH₂(2-MePr^(c)) Me CHO S 4-FPh 1091 CH₂(2-MePr^(c)) Me CHO NH 4-FPh 1092 CH₂CH═CH₂ Me CHO S 2,4-diFPh 1093 CH₂Pr^(c) Me CHO S 2,4-diFPh 1094 CH₂(2-MePr^(c)) Me CHO S 2,4-diFPh 1095 CH₂(2-MePr^(c)) Me CHO NH 2,4-diFPh 1096 CH₂CH═CH₂ Me CHO S 2-ClPh 1097 CH₂(2-MePr^(c)) Me CHO S 2-ClPh 1098 CH₂CH═CH₂ Me CHO S 4-ClPh 1099 CH₂Pr^(c) Me CHO S 4-ClPh 1100 CH₂(2-MePr^(c)) Me CHO S 4-ClPh 1101 CH₂(2-MePr^(c)) Me CHO NH 4-ClPh 1102 CH₂CH═CH₂ Me CHO S 2,4-diClPh 1103 CH₂Pr^(c) Me CHO S 2,4-diClPh 1104 CH₂(2-MePr^(c)) Me CHO S 2,4-diClPh 1105 CH₂(2-MePr^(c)) Me CHO NH 2,4-diClPh 1106 CH₂(2-MePr^(c)) Me CO₂H S Ph 1107 CH₂CH═CH₂ Me CO₂H S 2-FPh 1108 CH₂(2-MePr^(c)) Me CO₂H S 2-FPh 1109 CH₂CH═CH₂ Me CO₂H S 4-FPh 1110 CH₂CH═CH₂ Me CO₂H NH 4-FPh 1111 CH₂CH═CHCH₃ Me CO₂H S 4-FPh 1112 CH₂Pr^(c) Me CO₂H S 4-FPh 1113 CH₂(2-MePr^(c)) Me CO₂H S 4-FPh 1114 CH₂(2-MePr^(c)) Me CO₂H NH 4-FPh 1115 CH₂CH═CH₂ Me CO₂H S 2,4-diFPh 1116 CH₂Pr^(c) Me CO₂H S 2,4-diFPh 1117 CH₂(2-MePr^(c)) Me CO₂H S 2,4-diFPh 1118 CIH₂(2-MePr^(c)) Me CO₂H NH 2,4-diFPh 1119 CH₂CH═CH₂ Me CO₂H S 2-ClPh 1120 CH₂(2-MePr^(c)) Me CO₂H S 2-ClPh 1121 CH₂CH═CH₂ Me CO₂H S 4-ClPh 1122 CH₂Pr^(c) Me CO₂H S 4-ClPh 1123 CH₂(2-MePr^(c)) Me CO₂H S 4-ClPh 1124 CH₂(2-MePr^(c)) Me CO₂H NH 4-ClPh 1125 CH₂CH═CH₂ Me CO₂H S 2,4-diClPh 1126 CH₂Pr^(c) Me CO₂H S 2,4-diClPh 1127 CH₂(2-MePr^(c)) Me CO₂H S 2,4-diClPh 1128 CH₂(2-MePr^(c)) Me CO₂H NH 2,4-diClPh 1129 CH₂(2-MePr^(c)) Me CO₂Me S Ph 1130 CH₂(2-MePr^(c)) Me CO₂Me S 2-FPh 1131 CH₂CH═CH₂ Me CO₂Me S 4-FPh 1132 CH₂Pr^(c) Me CO₂Me S 4-FPh 1133 CH₂(2-MePr^(c)) Me CO₂Me S 4-FPh 1134 CH₂(2-MePr^(c)) Me CO₂Me NH 4-FPh 1135 CH₂CH═CH₂ Me CO₂Me S 2,4-diFPh 1136 CH₂(2-MePr^(c)) Me CO₂Me S 2,4-diFPh 1137 CH₂(2-MePr^(c)) Me CO₂Me NH 2,4-diFPh 1138 CH₂(2-MePr^(c)) Me CO₂Me S 2-ClPh 1139 CH₂CH═CH₂ Me CO₂Me S 4-ClPh 1140 CH₂(2-MePr^(c)) Me CO₂Me S 4-ClPh 1141 CH₂CH═CH₂ Me CO₂Me S 2,4-diClPh 1142 CH₂(2-MePr^(c)) Me CO₂Me S 2,4-diClPh 1143 CH₂(2-MePr^(c)) Me CO₂Me NH 2,4-diClPh I 144 CH₂(2-MePr^(c)) Me CO₂Et S Ph 1145 CH₂(2-MePr^(c)) Me CO₂Et S 2-FPh 1146 CH₂CH═CH₂ Me CO₂Et S 4-FPh 1147 CH₂Pr^(c) Me CO₂Et S 4-FPh 1148 CH₂(2-MePr^(c)) Me CO₂Et S 4-FPh 1149 CH₂(2-MePr^(c)) Me CO₂Et NH 4-FPh 1150 CH₂CH═CH₂ Me CO₂Et S 2,4-diFPh 1151 CH₂(2-MePr^(c)) Me CO₂Et S 2,4-diFPh 1152 CH₂(2-MePr^(c)) Me CO₂Et NH 2,4-diFPh 1153 CH₂(2-MePr^(c)) Me CO₂Et S 2-ClPh 1154 CH₂CH═CH₂ Me CO₂Et S 4-ClPh 1155 CH₂(2-MePr^(c)) Me CO₂Et S 4-ClPh 1156 CH₂CH═CH₂ Me CO₂Et S 2,4-diClPh 1157 CH₂(2-MePr^(c)) Me CO₂Et S 2,4-diClPh 1158 CH₂(2-MePr^(c)) Me CO₂Et NH 2,4-diClPh 1159 CH₂(2-MePr^(c)) Me CO₂Pr S 4-FPh 1160 CH₂(2-MePr^(c)) Me CO₂Bu S 4-FPh 1161 CH₂(2-MePr^(c)) Me CO₂Ph S 4-FPh 1162 CH₂CH═CH₂ Me CH₂OH O 2,6-diFPh 1163 CH₂CH═CHCH₃ Me CH₂OH O 2,6-diFPh 1164 CH₂Pr^(c) Me CH₂OH O 2,6-diFPh 1165 CH₂(2-MePr^(c)) Me CH₂OH O 2,6-diFPh 1166 CH₂CH═CH₂ Me CH₂OH O 2,6-diClPh 1167 CH₂CH═CHCH₃ Me CH₂OH O 2,6-diClPh 1168 CH₂Pr^(c) Me CH₂OH O 2,6-diClPh 1169 CH₂(2-MePr^(c)) Me CH₂OH O 2,6-diClPh 1170 CH₂CH═CH₂ Me CH₂OAc O 2,6-diFPh 1171 CH₂CH═CHCH₃ Me CH₂OAc O 2,6-diFPh 1172 CH₂Pr^(c) Me CH₂OAc O 2,6-diFPh 1173 CH₂(2-MePr^(c)) Me CH₂OAc O 2,6-diFPh 1174 CH₂CH═CH₂ Me CH₂OAc O 2,6-diFPh 1175 CH₂CH═CHCH₃ Me CH₂OAc O 2,6-diClPh 1176 CH₂Pr^(c) Me CH₂OAc O 2,6-diClPh 1177 CH₂(2-MePr^(c)) Me CH₂OAc O 2,6-diClPh 1178 CH₂CH═CH₂ Me CHO O 2,6-diFPh 1179 CH₂CH═CHCH₃ Me CHO O 2,6-diFPh 1180 CH₂Pr^(c) Me CHO O 2,6-diFPh 1181 CH₂(2-MePr^(c)) Me CHO O 2,6-diFPh 1182 CH₂CH═CH₂ Me CHO O 2,6-diClPh 1183 CH₂CH═CHCH₃ Me CHO O 2,6-diClPh 1184 CH₂Pr^(c) Me CHO O 2,6-diClPh 1185 CH₂(2-MePr^(c)) Me CHO O 2,6-diClPh 1186 CH₂CH═CH₂ Me CO₂H O 2,6-diFPh 1187 CH₂CH═CHCH₃ Me CO₂H O 2,6-diFPh 1188 CH₂Pr^(c) Me CO₂H O 2,6-diFPh 1189 CH₂(2-MePr^(c)) Me CO₂H O 2,6-diFph 1190 CH₂CH═CH₂ Me CO₂H O 2,6-diClPh 1191 CH₂CH═CHCH₃ Me CO₂H O 2,6-diClPh 1192 CH₂Pr^(c) Me CO₂H O 2,6-diClPh 1193 CH₂(2-MePr^(c)) Me CO₂H O 2,6-diClPh 1194 CH₂CH═CH₂ Et CH₂OH O 2,6-diFPh 1195 CH₂CH═CHCH₃ Et CH₂OH O 2,6-diFPh 1196 CH₂Pr^(c) Et CH₂OH O 2,6-diFPh 1197 CH₂(2-MePr^(c)) Et CH₂OH O 2,6-diFPh 1198 CH₂CH═CH₂ Et CH₂OH O 2,6-diClPh 1199 CH₂CH═CHCH₃ Et CH₂OH O 2,6-diClPh 1200 CH₂Pr^(c) Et CH₂OH O 2,6-diClPh 1201 CH₂(2-MePr^(c)) Et CH₂OH O 2,6-diClPh 1202 CH₂(2-MePr^(c)) Me CH₂OH S 2,6-diFPh 1203 CH₂(2-MePr^(c)) Me CH₂OH NH 2,6-diFPh 1204 CH₂(2-MePr^(c)) Me CH₂OH S 2,6-diClPh 1205 CH₂(2-MePr^(c)) Me CH₂OH NH 2,6-diClPh

[0079] Throughout the table 1 the following abbreviations are used with the following meanings.

[0080] Exemp. Comp. No.: Exemplification compound number,

[0081] Ac: acetyl, Bu: butyl, BU^(c): cyclobutyl, Bur: butyryl,

[0082] Et: ethyl, Hx^(c): cyclohexyl, Me: methyl, Pn^(c): cyclopentyl

[0083] Ph: phenyl, Pr: propyl, Prp : propionyl, Pr^(c): cyclopropyl.

[0084] In Table 1, preferred compounds are the compounds of Exemplification Compound numbers 2,4, 8, 9, 17, 19, 20, 21, 22, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 56, 59, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 82, 90, 93, 95, 105, 106, 114, 116, 120, 121, 129, 132, 134, 138, 140, 142, 144, 146, 167, 178, 188, 192, 196, 200, 216, 225, 233, 237, 241, 245, 264, 277, 286, 290, 294, 298, 306, 307, 310, 311, 317, 323, 326, 329, 332, 345, 351, 357, 360, 363, 366, 373, 377, 381, 383, 385, 387, 394, 411, 414, 415, 416, 417, 418, 419, 420,421, 422, 423, 424, 425, 426, 427, 430, 433, 436, 439, 442, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 461, 467, 470, 473, 476, 478, 480, 481, 482, 483, 484, 485, 486, 487, 488, 492, 494, 496, 498, 503, 504, 505, 506, 507, 508, 512, 514, 516, 518, 539, 542, 548, 558, 562, 564, 566, 583, 585, 589, 592, 594, 595, 596, 597, 598, 600, 602, 604, 606, 607, 608, 625, 626, 627, 633, 634, 665, 666, 667, 668, 669, 670, 671, 672, 675, 676, 681, 682, 683, 684, 685, 686, 702, 703, 704, 705, 706, 707, 723, 724, 725, 726, 727, 728, 834, 846, 858, 862, 889, 901, 930, 939, 990, 1014, 1018, 1072, 1090, 1094, 1113, 1117, 1133, 1136, 1148, 1149, 1159, 1163, 1164, 1165, 1167, 1169, 1171, 1173, 1175, 1177, 1181, 1185, 1189 and 1193.

[0085] More preferred compounds are the compounds of Exemplification Compound numbers 9, 19, 20, 22, 25, 32, 33, 40, 41, 43, 47, 48, 59, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 82, 93, 95, 105, 106, 114, 116, 120, 121, 134, 138, 142, 146, 167, 178, 311, 317, 416, 417, 420, 421, 427, 436, 439, 442, 450, 451, 454, 455, 461, 485, 506, 508, 589, 592, 594, 595, 596, 602, 606, 625, 633, 665, 666, 681, 682, 834, 846, 889, 1090, 1113, 1133, 1163, 1164, 1165, 1167, 1169, 1171, 1173, 1175 and 1177.

[0086] Further more preferred compounds are the compounds of Exemplification Compound numbers 9, 20, 22, 32, 33, 41, 43, 47, 48, 61, 63, 65, 69, 71, 73, 95, 106, 121, 421, 427, 455, 589, 594, 602, 606, 625, 1165 and 1169.

[0087] Still more preferred compounds are the compounds of Exemplification Compound numbers 22, 33, 43, 48, 106, 121, 421, 455 and 594.

[0088] Most preferred compounds are the compounds of:

[0089] Exemplification compound number 22: 1-(2-butenyl)-7-(4-fluorobenzyloxy)-3-hydroxymethyl-2-methylpyrrolo[2,3-d]pyridazine,

[0090] Exemplification compound number 33: 7-(4fluorobenzyloxy)-3-hydroxymethyl-2-methyl-1-(2-methylcyclopropylmethyl)pyrrolo[2,3-d]pyridazine,

[0091] Exemplification compound number 43: 1-(2-butenyl)-7-(2,4difluorobenzyloxy)-3-hydroxymethyl-2-methylpyrrolo[2,3-d]pyridazine,

[0092] Exemplification compound number 48: 7-(2,4-difluorobenzyloxy)-3-hydroxymethyl-2-methyl-1-(2-methylcyclopropylmethyl)pyrrolo[2,3-d]pyridazine,

[0093] Exemplification compound number 106: 3-acetoxymethyl-7-4fluorobenzyloxy)-2-methyl-1-(2-methylcyclopropylmethyl)pyrrolo[2,3-d]pyridazine, and

[0094] Exemplification compound number 121: 3-acetoxymethyl-7-(2,4difluorobenzyloxy)-2-methyl-1-(2-methylcyclopropylmethyl)pyrrolo[2,3-d]pyridazine.

[0095] In addition, of the compounds described above, 1-[(1S,2S)-2-methylcyclopropylmethyl] derivatives are preferred compounds.

[0096] The pyrrolopyridazine compounds of formula (I) can be prepared according to the following method.

[0097] In the above reaction scheme R¹, R², R⁴ and A have the same meanings as described above.

[0098] The step 1 is a process preparing a compound of formula (Ia) and is accomplished by reaction of a compound of formula (II) with an oxidizing agent in an inert solvent.

[0099] The oxidizing agent employed is, for example, an oxidizing agent by which a methyl group can be converted into a hydroxymethyl group, such as ammonium cerium (IV) nitrate, manganese (III) acetate or selenium dioxide; preferably ammonium cerium (IV) nitrate. The amount of the oxidizing agent is from 1.5 to 10 (preferably 2 to 6) moles to one mole of the compound of formula (II).

[0100] The employed inert solvent is not particularly limited provided that it has no adverse effect on the reaction and can dissolve the starting materials to a certain extent. Such a solvent is, for example, a halogeno-hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, or dichlorobenzene; an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or diethylene glycol dimethyl ether; a carboxylic acid or a carboxylic acid anhydride such as acetic acid, acetic anhydride, propionic acid, or benzoic acid; water; or mixtures thereof; and is preferably a carboxylic acid, a carboxylic acid anhydride, a carboxylic acid containing water or a mixture of a carboxylic acid and a carboxylic acid anhydride; and is more preferably acetic acid, acetic anhydride, acetic acid containing water or a mixture of acetic acid and acetic anhydride.

[0101] The reaction temperature is usually from 0° C. to 150° C. (preferably from room temperature to 100° C.). The reaction time varies depending on the reaction temperature and other factors but it is from 30 minutes to 20 hours (preferably from 1 hour to 10 hours).

[0102] When a carboxylic acid or a carboxylic acid anhydride is used as the inert solvent in the step 1, in certain cases a product esterified at the hydroxymethyl group of compound (Ia) by the carboxylic acid can be obtained. The esterified compound is hydrolyzed according to a conventional method to give the compound of formula (Ia). For example the esterified compound is treated with a base (for example an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, or potassium hydroxide; or an alkali metal carbonate such as sodium carbonate, potassium carbonate; preferably an alkali metal hydroxide and most preferably lithium hydroxide) at from 0° C. to 100° C. (preferably from 10° C. to 50° C.) for from 10 minutes to 10 hours (preferably from 20 minutes to 5 hours) in an inert solvent containing water (for example, an alcohol containing water such as methanol containing water or ethanol containing water) to give a compound of formula (Ia).

[0103] A compound of formula (Id), which is a compound of formula (I) wherein R³ is a C₂-C₆ aliphatic acyloxymethyl group, a C₆-C₁₀arylcarbonyloxymethyl group which may be optionally substituted with substituents selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy and halogeno, or a C₁-C₆ alkoxycarbonyloxymethyl group, can be prepared by acylation of a compound of formula (Ia).

[0104] In the formula of (Id), R⁵ represents a C₂-C₆ aliphatic acyl group, a C₆-C₁₀ arylcarbonyl group which may be optionally substituted with substituents selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy and halogeno, or a C₁-C₆ alkoxycarbonyl group, and R¹, R², R⁴ and A have the same meanings as described above.

[0105] The acylating reagent is, for example, a C₂-C₆ aliphatic acyl halide such as acetyl chloride, acetyl bromide, propionyl chloride, propionyl bromide, butyryl chloride, isobutyryl chloride, valeryl chloride, or hexanoyl chloride; a C₂-C₆ aliphatic carboxylic acid anhydride such as acetic anhydride, propionic anhydride, or hexanoic anhydride; a C₆-C₁₀ arylcarbonyl halide which may be optionally substituted with substituents selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy and halogeno, such as benzoyl chloride, benzoyl bromide, toluoyl chloride, toluoyl bromide, methoxybenzoyl chloride, chlorobenzoyl chloride, fluorobenzoyl chloride, or naphthoyl chloride; or a C₁-C₆ alkoxycarbonyl halide such as methoxycarbonyl chloride, ethoxycarbonyl chloride, ethoxycarbonyl bromide, propoxycarbonyl chloride, butoxycarbonyl chloride, pentyloxycarbonyl chloride, or hexyloxycarbonyl chloride; preferably a C₂-C₆ aliphatic acyl chloride, a C₆-C₁₀ arylcarbonyl chloride which may be optionally substituted with substituents selected from the group consisting of C₁-C₆ alkyl C₁-C₆ alkoxy and halogeno or a C₁-C₆ alkoxycarbonyl chloride.

[0106] The employed base is, for example, an alkali metal amide such as lithium amide, sodium amide, or potassium amide; an alkali metal carbonate such as lithium carbonate, sodium carbonate, or potassium carbonate; an alkali metal alkoxide such as lithium methoxide, sodium methoxide, sodium ethoxide, or potassium t-butoxide; or an organic amine such as triethylamine, tributylamine, diisopropylethylamine, N-ethylmorpholine, pyridine, picoline, 4-(N,N-dimethylamino)pyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); preferably an organic amine and most preferably triethylamine or pyridine.

[0107] The employed inert solvent is not particularly limited provided that it has no adverse effect on the reaction and can dissolve the starting materials to a certain extent. Such a solvent is, for example, an aromatic hydrocarbon such as benzene, toluene, or xylene; a halogeno-hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, or dichlorobenzene; an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or diethylene glycol dimethyl ether-, or mixtures thereof; and is preferably a halogeno-hydrocarbon or an ether; and is more preferably methylene chloride, chloroform, diethyl ether or tetrahydrofuran.

[0108] The reaction temperature is usually from 0° C. to 100° C. (preferably from 10° C. to 50° C.). The reaction time varies depending on the reaction temperature and other factors but it is from 10 minutes to 100 hours (preferably from 30 minutes to 5 hours).

[0109] The step 2 is a process for preparing a compound of formula (Ib) and is accomplished by reaction of a compound of formula (Ia) with an oxidizing agent in an inert solvent.

[0110] The employed oxidizing agent is, for example, an oxidizing agent by which a hydroxymethyl group can be converted into a formyl group, such as manganese dioxide, pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), or a mixture of dimethyl sulfoxide and an acid anhydride (for example an aliphatic carboxylic acid anhydride which may be optionally substituted with halogeno, such as acetic anhydride, trifluoroacetic anhydride, or propionic anhydride; preferably acetic anhydride or trifluoroacetic anhydride); preferably manganese dioxide. The amount of the oxidizing agent is usually from 1 to 50 (preferably 2 to 30) moles to one mole of the compound of formula (Ia).

[0111] The employed inert solvent is not particularly limited provided that it has no adverse effect on the reaction and can dissolve the starting materials to a certain extent. Such a solvent is, for example, an aromatic hydrocarbon such as benzene, toluene, or xylene; a halogeno-hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, or dichlorobenzene; an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or diethylene glycol dimethyl ether; or mixtures thereof; and is preferably a halogeno-hydrocarbon; and is most preferably methylene chloride.

[0112] The reaction temperature is usually from 0° C. to 150° C. (preferably from room temperature to 100° C.). The reaction time varies depending on the reaction temperature and other factors but it is from 30 minutes to 40 hours (preferably from 1 hour to 20 hours).

[0113] The step 3 is a process preparing a compound of formula (Ic) and is accomplished by reaction of a compound of formula (Ib) with an oxidizing agent in an inert solvent.

[0114] The employed oxidizing agent is, for example, an oxidizing agent by which a formyl group can be converted into a carboxyl group, such as silver oxide, pyridinium chlorochromate (PCC), or pyridinium dichromate (PDC); preferably silver oxide. The amount of the oxidizing agent is usually from 1 to 20 (preferably 2 to 10) moles to one mole of the compound of formula (Ib). When silver oxide is used as an oxidizing agent, silver oxide prepared by reaction of silver nitrate with an alkali metal hydroxide (preferably sodium hydroxide) is preferably used.

[0115] The employed inert solvent is not particularly limited provided that it has no adverse effect on the reaction and can dissolve the starting materials to a certain extent. Such a solvent is, for example, a halogeno-hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, or dichlorobenzene; an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or diethylene glycol dimethyl ether; an alcohol such as methanol, or ethanol; a carboxylic acid such as acetic acid, propionic acid, or benzoic acid; water; or mixtures thereof; and is preferably an alcohol, an alchohol containing water, a carboxylic acid, a carboxylic acid containing water or water; and is more preferably an alcohol containing water; and is most preferably ethanol containing water.

[0116] The reaction temperature is usually from 0° C. to 150° C. (preferably from room temperature to 100° C.). The reaction time varies depending on the reaction temperature and other factors but it is from 1 hour to 72 hours (preferably from 12 hours to 48 hours).

[0117] A compound of formula (Ie), which is a compound of formula (I) wherein R³ is a C₁-C₆ alkoxycarbonyl group or a C₆-C₁₀ aryloxycarbonyl group which may be optionally substituted with substituents selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy and halogeno, can be prepared by esterification of a compound of formula (Ic).

[0118] In the formula (Ie), R⁶ represents a C₁-C₆ alkyl group, or a C₆-C₁₀ aryl group which may be optionally substituted with substituents selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy and halogeno and R¹, R², R⁴ and A have the same meanings as described above.

[0119] The esterification is accomplished by reaction of a compound of formula (Ic) with a halogenating agent in an inert solvent to afford a carboxylic acid halide, followed by reaction of the carboxylic acid halide with an alcohol or a phenol derivative in the presence of a base in an inert solvent. The two step reactions can be carried out in a single reaction vessel, wherein the compound of formula (Ic) is reacted with a halogenating agent and, if necessary, the solvent can be removed from the reaction mixture.

[0120] The halogenating agent employed is, for example, a thionyl halide such as thionyl chloride, thionyl bromide or a phosphorus halide such as phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, or phosphorus oxybromide; preferably thionyl chloride or phosphorus oxychloride.

[0121] The inert solvent employed in the reaction of the compound of formula (Ic) with a halogenating agent is not particularly limited provided that it has no adverse effect on the reaction and can dissolve the starting materials to a certain extent. Such a solvent is, for example, an aromatic hydrocarbon such as benzene, toluene, or xylene; a halogeno-hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, or dichlorobenzene; an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or diethylene glycol dimethyl ether; or mixtures thereof; and is preferably an ether; and is most preferably diethyl ether or tetrahydrofuran.

[0122] The reaction temperature is usually from 0° C. to 100° C. (preferably 10° C. to 50° C.). The reaction time varies depending on the reaction temperature and other factors but it is from 10 minutes to 10 hours (preferably from 30 minutes to 5 hours).

[0123] The inert solvent employed in the reaction of the carboxylic acid halide with an alcohol or phenol derivative is the same solvent as described in the reaction of the compound of formula (Ic) with a halogenating agent. The reaction temperature and the time required for the reaction are in the same range as described in the reaction of the compound of formula (Ic) with a halogenating agent.

[0124] In each step described above each desired compound may be isolated by conventional procedures from the reaction mixture. For example, it may be obtained 1) by filtration of the reaction mixture when insoluble material exists in the reaction mixture, followed by evaporation of the solvent of the filtrate; or by 1) concentration of the reaction mixture, 2) addition of water to the residue followed by partition between water and an appropriate organic solvent immiscible with water, 3) drying the extract over anhydrous magnesium sulfate and the like, followed by 4) concentration of the extract. The desired compound can be, if necessary, be further purified by conventional procedures such as recrystallization, column chromatography and the like.

[0125] A compound of formula (I) can be transformed into a pharmaceutically acceptable salt thereof by treatment of the compound of formula (I) with an acid according to a conventional technique. For example the desired salt can be obtained by reaction of a compound of formula (I) with an acid in an inert solvent (preferably an ether such as diethyl ether, tetrahydrofuran, or dioxane; an alcohol such as methanol, ethanol, or propanol; or a halogeno-hydrocarbon such as methylene chloride, or chloroform) at room temperature for from 5 minutes to 1 hour, followed by evaporation of the solvent.

[0126] The starting compound of formula (II) is known or can easily be prepared by the reaction of a pyrrole compound of formula (III) with a compound of formula R¹-X (IV) according to a known method (for example Japanese Patent Application Publication Hei 7-247285);

[0127] wherein R⁷ represents a C₁-C₆ alkyl group, R² has the same meanings as described above, X represents a halogen atom (preferably a chlorine or bromine atom), and R¹ has the same meanings as described above.

[0128] The compounds of formula (III) and (IV) are also known or can easily be obtained by a known procedure (for example Japanese Patent Application Publication Hei 7-247825; Monatschefte fur Chemie (1973), 104, 925; J. Chem. Soc., Perkin.Trans.II (1979) 287 and the like).

[0129] In addition each desired optically active compound of formula (I) and (IV) (for example 1S,2S-form) can be obtained by optical resolution of a racemic form of the corresponding compound (a mixture of 1S,2S-form and IR,2R-form and the like). The optical resolution can be carried out by an appropriate selection from conventional techniques such as chromatography on a column for optical resolution, preferential crystallization, and resolution of a mixture of diastereomeric salts.

[0130] The compounds of formula (I) or pharmaceutically acceptable salts thereof of this invention exhibit potent gastric acid secretion inhibition activity, gastric mucous membrane protection activity and potent antibacterial activity against Helicobacter pylori and they have excellent properties as a medicament. The compounds of formula (I) or pharmaceutically acceptable salts thereof are useful as a prophylactic or therapeutic medicament for the prevention and treatment of ulcerative diseases such as peptic ulcer, acute or chronic gastric ulcer, gastrisis, reflux esophagitis, gastroesophageal reflux disorder, dyspepsia, gastric hyperacidity, Zollinger-Ellison syndrome etc. and for bacterial infections arising from Helicobacter pylori.

[0131] When used as a prophylactic or therapeutic medicament for the diseases described above, a compound of formula (I) or a pharmaceutically acceptable salt thereof (the active ingredient) can be administered alone or can be presented as part of a pharmaceutical formulation. The pharmaceutical formulation is prepared by blending the active ingredient with appropriate pharmaceutically acceptable carriers, e.g., excipients, diluents and the like, followed by formulation in the form of tablets, capsules, granules, powders or syrups and the like for oral administration or in the form of injections and the like for parenteral administration (preferably oral administration).

[0132] The production of such pharmaceutical formulations is carried out according to general techniques known to those skilled in the art using carriers which may includes such additives as an excipient, a binder, a disintegrant, a lubricant, a stabilizer, a corrigent, a diluent and a solvent for injections.

[0133] The excipient is, for example, a sugar derivative such as lactose, sucrose, glucose, mannitol, or sorbitol; a starch derivative such as corn starch, potato starch, α-starch, dextrin, or carboxymethyl starch; a cellulose derivative such as crystalline cellulose, low-substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, or internally bridged sodium carboxymethyl cellulose; acacia; dextran; pullulan; a silicate derivative such as light silicic acid anhydride, synthetic aluminium silicate, or magnesium aluminate meta-silicate; a phosphonate derivative such as calcium phosphonate; a carbonate derivative such as calcium carbonate; a sulfate derivative such as calcium sulfate; and the like.

[0134] The binder is, for example, one of the excipients described above; gelatin; polyvinylpyrrolidone; macrogol (trade mark) and the like.

[0135] The disintegrant is, for example, one of the excipients described above; a chemically modified starch or cellulose derivative such as sodium croscarmellose or sodium carboxymethyl starch; bridged polyvinylpyrrolidone; and the like.

[0136] The lubricant is, for example, talc; stearic acid; a metal salt of stearic acid such as calcium stearate, or magnesium stearate; colloidal silica; a wax such as bee gum and spermaceti; boric acid; glycol; a carboxylic acid such as fumaric acid, or adipic acid; a sodium carboxylate such as sodium benzoate; a sulfate such as sodium sulfate; leucine; a laurylsulfate such as sodium laurylsulfate, or magnesium laurylsulfate; a silicic acid such as silicic acid anhydride, or a silicic acid hydrate; one of the starch derivatives described above in relation to the excipients; and the like.

[0137] The stabilizer is, for example, a p-hydroxybenzoate derivative such as methylparaben, or propylparaben; an alcohol such as chlorobutanol, benzyl alcohol, or phenylethyl alcohol; benzalkonium chloride; a phenol derivative such as phenol, or cresol; thimerosal; dehydroacetic acid; sorbic acid; and the like.

[0138] The corrigent is, for example, a sweetening, souring, or flavoring agent, which are conventionally used; and the like.

[0139] The solvent for injection is, for example, water, ethanol, glycerin and the like.

[0140] Suitable dosage levels will depend on the condition of the patient, human or other animal, the disease, whether the drug administration is for prevention or treatment, the age of the patient and the like, but typically suitable dosage levels for an active ingredient of the present invention are from 1 mg (preferably 5 mg) to 1000 mg (preferably 500 mg) for oral administration and from 0.1 mg (preferably 1 mg) to 500 mg (preferably 300 mg) for intravenous administration per unit dose, per day, for an adult human, respectively. The dosages described above are preferably administered from one time to six times throughout the day, depending on the condition of the disease.

[0141] The following Examples, Reference Examples, Test Examples and Formulation Examples are intended to further illustrate the present invention and are not intended to limit the scope of the invention.

EXAMPLE 1 3-Acetoxymethyl-7-(4-fluorobenzyloxy)-2-methyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]-pyridazine

[0142] To a solution of 7-(4-fluorobenzyloxy)-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridazine (0.679 g, 2.00 mmol) in acetic acid (40 ml) was added ammonium cerium (IV) nitrate (6.58 g, 12.0 mmol) at room temperature. The mixture was stirred at 60° C. for 3 hours, poured into water and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel column using hexane/ethyl acetate=1/1 as the eluant to afford an oil which was crystallized in hexane to give the title compound (0.255 g, 28%) as pale yellow crystals.

[0143] Melting point: 122-123° C. Mass spectrum (CI, m/z): 398 (M⁺+1). NMR spectrum CDCl₃, δppm): 0.13-0.20 (m, 1H), 0.37-0.44 (m, 1H), 0.61-0.68 (m, 1H), 0.84-0.91 (m, 1H), 0.90 (d; J=5.9 Hz, 3H), 2.05 (s, 3H), 2.48 (s, 3H), 4.14 (dd; J=14.6 Hz, 7.3 Hz, 1H), 4.31 (dd; J=14.6 Hz, 6.3 Hz, 1H), 5.27 (s, 2H), 5.65 J=12.0 Hz, 1H), 5.70 (d; J=12.0 Hz, 1H), 7.05-7.12 (m, 2H), 7.48-7.53 (m,2H), 9.12 (s, 1H).

EXAMPLE 2

[0144] 7-(4-Fluorobenzyloxy)-3-hydroxymethyl-2-methyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]-pyridazine

[0145] To a solution of 7-(4-fluorobenzyloxy)-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3d]pyridazine (67.9 g, 200 mmol) in acetic acid (800 ml) was added ammonium cerium (IV) nitrate (329 g, 600 mmol) at room temperature. The mixture was stirred at 55° C. for 8 hours, poured into water and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. To the residue were added methanol (500 ml) and a 2N aqueous lithium hydroxide solution (160 ml) and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was neutralized with 1N hydrochloric acid and the methanol was evaporated off in vacuo. The resulting mixture was extracted with chloroform. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel column using ethyl acetate and ethyl acetate/methanol=9/1 as the eluant to afford crystals which were washed with ethyl acetate to give the title compound (24.6 g, 35%) as pale yellow crystals.

[0146] Melting point: 128-129° C. Mass spectrum (CI, m/z): 356 (M⁺+1). NMR spectrum CDCl₃, δppm): 0.10-0.16 (m, 1H), 0.340.40 (m, 1H), 0.58-0.68 (m, 1H), 0.77-0.86 (m, 1H), 0.87 (d; J=5.9 Hz, 3H), 2.44 (s, 3H), 4.09 (dd; J=14.6 Hz, 7.3 Hz, 1H), 4.26 (dd; J=14.6 Hz, 6.3 Hz, 1H), 4.82 (s, 2H), 5.57 (d; J=11.7 Hz, 1H), 5.62 (d; J=11.7 Hz, 1H), 7.04-7.09 (m, 2H), 7.47 (dd; J=8.8 Hz, 5.4 Hz, 2H), 9.07 (s, 1H). Optical rotation: [α]_(D) ²⁰ =+18.2°(C=1.00, MeOH).

EXAMPLE 3 7-(4-Fluorobenzyloxy)-3-formyl-2-methyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridazine

[0147] To a solution of 7-(4-fluorobenzyloxy)-3-hydroxymethyl-2-methyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridazine (64.3 g, 181 mmol) in methylene chloride (900 ml) was added activated manganese dioxide (472 g, 5.43 mol) at room temperature. The mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered through celite (trade mark) and the filtrate was concentrated in vacuo. The crude crystals (45.7 g) were washed with ethyl acetate and hexane to give the title compound (44.3 g, 69%) as pale yellow crystals.

[0148] Melting point: 138.5-139.5° C. Mass spectrum (CI, m/z): 354 (M⁺+1). NMR spectrum (CDCl₃, δppm): 0.19-0.26 (m, 1H), 0.40-0.47 (m, 1H), 0.71-0.78 (m, 1H), 0.84-0.91 (m, 1H), 0.92 (d; J=5.9 Hz, 3H), 2.75 (s, 3H), 4.19 (dd; J=14.6 Hz, 7.1 Hz, 1H), 4.35 (dd; J=14.6 Hz, 6.6 Hz, 1H), 5.67 (d; J=12.0 Hz, 1H), 5.73 (d; J=12.0 Hz, 1H), 7.07-7.14 (m, 2H), 7.51 (dd; J=8.5 Hz, 5.4 Hz, 2H), 9.63 (s, 1H), 10.22 (s, 1H).

[0149] Optical rotation: [α]_(D) ²⁰=+20.4° (C=1.00, MeOH).

EXAMPLE 4 3-Carboxy-7-(4-fluorobenzyloxy)-2-methyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2.3-d]pyridazine

[0150] To a solution of silver nitrate (0.85 g, 5 mmol) in water (2.5 ml) was added an aqueous 2N lithium hydroxide solution (3 ml), followed by a solution of 7-(4-fluorobenzyloxy)-3-formyl-2-methyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridazine (0.177 g, 0.5 mmol) in ethanol (10 ml). The mixture was stirred at room temperature for 48 hours. To the reaction mixture was added 1N hydrochloric acid (3 ml) and the resulting mixture was filtered through celite (trade mark). The celite (trade mark) was washed with ethanol (30 ml). To the combined filtrates was added water and the resulting mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel column using chloroform/isopropanol=19/1 as the eluant to give the title compound (0.094 g, 51%) as pale yellow crystals.

[0151] Melting point: 170-225° C. Mass spectrum (CI, m/z): 370 (M⁺+1). NMR spectrum CDCl₃, δppm) : 0.20-0.25 (m, 1H), 0.40-0.46 (m, 1H), 0.63-0.69 (m, 1H), 0.86-0.92 (m, 1H), 0.91 (d; J=5.9 Hz, 3H), 2.86 (s, 3H), 3.60 (bs, 1H), 4.26 (dd; J=14.7 Hz, 7.3 Hz, 1H), 4.40 (dd; J=14.7 Hz, 6.8 Hz, 1H), 5.67 (d; J=11.7 Hz, 1H), 5.72 (d; J=11.7 Hz, 1H), 7.08-7.14 (m, 2H), 7.53 (dd; J=8.8 Hz, 5.4 Hz, 2H), 9.88 (bs, 1H). Optical rotation: [α]_(D) ²⁰=+15.8° (C=1.00, MeOH),

Reference Example 1 7-(4-Fluorobenzyloxy)-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-]-pyridazine

[0152] (a) Methyl 3-formyl-4,5-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrole-2-carboxylate

[0153] Potassium tert-butoxide (3.49 g, 35.1 mmol) was added to a solution of methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate (5.79 g, 31.9 mmol) and 18-crown-6 (0.41 g, 1.55 mmol) in tetrahydrofuran (130 ml) and the mixture was stirred at room temperature for 1 hour. After dropwise addition over 30 minutes of (1S,2S)-2-methylcyclopropylmethyl bromide (5.71 g, 38.3 mmol) to the reaction mixture at 50° C., the mixture was heated under reflux for 3 hours. Potassium tert-butoxide (0.36 g, 3.22 mmol) and (1S,2S)-2-methylcyclopropylmethyl bromide (0.48 g, 3.21 mmol) were further added to the mixture and this mixture was heated for 1 hour. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to afford the desired compound (8.26 g, 100%) as a pale brown oil.

[0154] Mass spectrum (CI, m/z): 250 (M⁺+1) NMR spectrum CDCl₃, δppm) : 0.25 (dt; J=8 Hz, 5 Hz, 1H), 0.48 (dt; J=8 Hz, 5 Hz 1H), 0.71-0.80 (m, 1H), 0.82-0.89 (m, 1H), 1.00 (d; J=6 Hz, 3H), 2.20 (s, 3H), 3.89 (s, 3H), 4.25 (d; J=7 Hz, 2H), 10.43 (s, 1H). Optical rotation: [α]_(D) ²⁰=+17.6° (C=1.02, EtOH).

[0155] (b) 2,3-Dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]-6,7-dihydropyrrolo]2,3-d]pyridazine-7-one

[0156] Hydrazine hydrate (1.92 g, 38.4 mmol) was added to a solution of methyl 3-formyl-4,5-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrole-2-carboxylate (7.96 g 31.9 mmol) in acetic acid (38 ml) at room temperature and the mixture was stirred at 90° C. for 1hour. After the reaction was completed, the reaction mixture was cooled to room temperature and poured into ice-water. The crude crystals were collected by filtration, washed with water and dissolved in a mixture of chloroform and methanol (9:1). The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and to the residue was added a mixture of toluene and hexane. The precipitate was collected by filtration to afford the desired compound (7.02 g, 95.0%) as a pale yellowish white powder.

[0157] Mass spectrum (CI, m/z): 232 (M⁺+1) NMR spectrum (CDCl₃, δppm): 0.22 (dt; J=8 Hz, 5 Hz, 1H), 0.64 (dt; J=8 Hz, 5 Hz, 1H), 0.86-0.95 (m, 2H), 0.98 (d; J=5 Hz, 3H), 2.21 (s, 3H), 2.35 (s, 3H), 4.44(d; J=7 Hz, 2Hl), 8.05 (s, 1H), 9.97 (s, 1H). Optical rotation: [α]_(D) ²⁰=+11.2° (C=0.50, EtOH).

[0158] (c) 7-Chloro-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo2,3-d]pyridazine

[0159] Phosphorus oxychloride (55 ml, 590 mmol) was added to 2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]-6,7-dihydropyrrolo[2,3-d]pyridazine-7-one (6.95 g, 30.1 mmol) and the mixture was stirred at 90° C. for 3.5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and poured into ice-water. The aqueous solution was neutralized with a 5N aqueous sodium hydroxide solution and extracted with methylene chloride. The extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated in vacuo. Hexane was added to the residue and the precipitate was collected by filtration to afford the desired compound (6.90 g, 92.0%) as a pale yellow powder.

[0160] Mass spectrum (CI, m/z): 250 (M⁺+1) NMR spectrum CDCl₃, δppm): 0.29 (dt; J=8 Hz, 5 Hz, 1H), 0.54 (dt; J=8 Hz, 5 Hz, 1H), 0.73-1.02 (m, 5H), 2.30 (s, 3H), 2.43 (s, 3H), 4.44 (d; J=6 Hz, 2H), 9.15 (s,1H). Optical rotation: [α]_(D) ²⁰+12.3° (C=1.01, EtOH).

[0161] (d) 7-(4-Fluorobenzyloxy)-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]-pyridazine

[0162] A solution of p-fluorobenzyl alcohol (1.45 g, 11.5 mmol) in tetrahydrofuran (2 ml) was added dropwise to a solution of sodium hydride (0.26 g, 10.8 mmol) in tetrahydrofuran (6 ml) and the mixture was stirred at room temperature for 30 minutes. A solution of 7-chloro-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridazine (2.50 g, 10.0 mmol) in tetrahydrofuran (13 ml) was added dropwise to the reaction mixture at room temperature and the mixture was heated under reflux for 3 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated in vacuo. Hexane was added to the concentrated solution, and the precipitate was collected by filtration and then recrystallized from a mixture of ethyl acetate and hexane to afford the title compound (2.25 g, 66.4%) as pale brown crystals.

[0163] Mp: 114-115° C. Mass spectrum (CI, m/z): 340 (M⁺+1) 1H-NMR spectrum (CDCl₃, δppm): 0.14 (dt; J=8 Hz, 5 Hz, 1H), 0.39 (dt; J=8 Hz, 5 Hz, 1H), 0.59-0.65 (m, 1H), 0.76-0.85 (m, 1H), 0.89 (d; J=6 Hz, 3H), 2.26 (s,3H), 2.36 (s, 3H), 4.13 (dd; J=15 Hz, 7 Hz, 1H), 4.27 (dd; J=15 Hz, 6 Hz, 1H), J=12 Hz, 1H), 5.68 (d; J=12 Hz, 1H), 7.05-7.12 (m, 2H), 7.47-7.52 (m, 2H), 8.96 (s, 1H). Optical rotation: [α]_(D) ²⁰=+17.9° (C=0.50, EtOH).

Reference Example 2 Methyl 3-formyl-4,5-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrole-2-carboxylate

[0164] (a) Methyl-4,5-dimethyl-1-[(E)-2-methylcyclopropylmethyl]pyrrole-2-carboxylate

[0165] Potassium tert-butoxide (18.33 g, 164 mmol) was added to a solution of methyl 4,5-dimethylpyrrole-2-carboxylate (25.02 g, 163 mmol) and 18-crown-6 (3.19 g, 12.1 mmol) in tetrahydrofuran (150 ml) and the mixture was stirred at room temperature for 1 hour. To this mixture was added a solution of (E)-2-methylcyclopropylmethyl bromide (racemate, 12.70 g, 85.2 mmol) and the mixture was heated under reflux for 7 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated in vacuo. The residue was chromatographed on a column using toluene as the eluant to afford the desired compound (racemate, 13.50 g, 71.6%) as a brown oil.

[0166] Mass spectrum (CI, m/z): 222 (M⁺+1) NMR spectrum (CDCl₃, δppm): 0.20 (dt; J=8 Hz, 5 Hz, 1H), 0.48 (dt; J=8 Hz, 5 Hz, 1H), 0.67-0.93 (m, 2H), 0.98 (d; J=6 Hz, 3H), 2.01 (s, 3H), 2.18 (s, 3H), 3.76 (s,3H) 4.21 (d; J=7 Hz, 2H), 6.76 (s, 1H).

[0167] (b) Methyl 4,5-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrole-2-carboxylate

[0168] Methyl 4,5-dimethyl-1-[(E)-2-methylcyclopropylmethyl]pyrrole-2-carboxylate (10.00 g) was chromatographed by high pressure liquid chromatography to afford the title [(S,S) form] compound (3.33 g) and the [(R,R) form] compound (3.97 g), which is the antipode of the [(S,S) form] compound.

[0169] Separation conditions;

[0170] Column: CHIRALCEL OJ, 50Φ×500 mm, Daicel Chemical Industries, Ltd.

[0171] Eluant: hexane/2-propanol=1000/1

[0172] Flow rate: 25 ml per minute

[0173] The title [(S,S) form] compound:

[0174] Mass spectrum (CI, m/z): 222 (M⁺+1) NMR spectrum CDCl₃, δppm): 0.20 (dt; J=8 Hz, 5 Hz, 1H), 0.48 (dt; J=8 Hz, 5 Hz, 1H), 0.66-0.80 (m, 1H), 0.82-0.91 (m, 1H), 0.98 (d; J=6 Hz, 3H), 2.01 (s, 3H), 3.76 (s, 3H), 4.21 (d; J=7 Hz, 2H), 6.76 (s, 1H). Optical rotation: [α]_(D) ²⁰=+17.6° (C=1.00, EtOH).

[0175] The antipode [(R,R) form] compound: Mass spectrum (CI, m/z): 222 (M⁺+1) NMR spectrum (CDCl₃, δppm): 0.20 (dt; J=8 Hz, 5 Hz, 1H), 0.48 (dt; J=8 Hz, 5 Hz, 1H), 0.66-0.80 (m, 1H), 0.82-0.91 (m, 1H), 0.98 (d; J=6 Hz, 3H), 2.01 (s,3H),2.18 (s, 3H), 3.77 (s, 3H), 4.21 (d; J=7 Hz, 2H), 6.76 (s, 1H). Optical rotation: [α]_(D) ²⁰=−17.0° (C=1.01, EtOH).

[0176] (c) Methyl 3-formyl-4,5-dimethyl-1-[(1S 2S)-2-methylcyclopropylmethyl]pyrrole-2 -carboxylate

[0177] Phosphorus oxychloride (2.15 g, 14 mmol) was added to a solution of dimethylformamide (1.10 g, 15 mmol) in toluene (2 ml) and the mixture was stirred at room temperature for 30 minutes. To this mixture was added a solution of methyl 4,5-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrole-2-carboxylate (2.21 g, 10 mmol) in toluene (6 ml) and the mixture was heated at 80° C. for 10 hours. After the reaction was completed, the reaction mixture was poured into water and neutralized with a saturated aqueous sodium hydrogencarbonate solution. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated in vacuo. The residue was chromatographed on a column using ethyl acetate/hexane=10/1 as the eluant to afford the title compound (1.95 g, 78.2%) as a pale yellow oil.

Reference Example 3 7-(4-Fluorobenzyloxy)-2,3-dimethyl-1-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2.3-d]-pyridazine (a) 7-(4-Fluorobenzyloxy)-1-[(E)-2-methylcyclopropylmethyl]-2,3-dimethylpyrrolo[2,3-d]pyridazine (racemate)

[0178] A reaction was carried out in a similar manner to that described in Reference example 1 using (E)-2-methylcyclopropylmethyl bromide (racemate) instead of (1S,2S)-2-methylcyclopropylmethyl bromide to afford the desired compound (56%).

[0179] Mp: 120-122° C. Mass spectrum (CI, m/z): 340 (M⁺+1) 1H-NMR spectrum CDCl₃, δppm): 0.14 (dt; J=8 Hz, 5 Hz, 1H), 0.39 (dt; J=8 Hz, 5 Hz, 1H), 0.59-0.65 (m, 1H), 0.76-0.85 (m, 1H), 0.89 (d; J=6 Hz, 3H), 2.26 (s, 3H), 2.36 (s, 3H), 4.13 (dd; J=15 Hz, 7 Hz, 1H), 4.27 (dd; J=15 Hz, 6 Hz, 1H), 5.63 (d; J=12 Hz, 1H), 5.68 (d; J=12 Hz, 1H), 7.05-7.12 (m, 2H), 7.47-7.52 (m, 2H), 8.96(s, 1H).

[0180] (b) 7-(4-Fluorobenzyloxy)-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridazine

[0181] 7-(4-Fluorobenzyloxy)-1-[(E)-2-methylcyclopropylmethyl]-2,3-dimethylpyrrolo[2,3-d]pyridazine (racemate, 25 g) was chromatographed by high pressure liquid chromatography and recrystallized from ethyl acetate to afford the title [(S,S) form] compound (8.54 g) and the [(R,R) form] compound (7.60 g), which is the antipode of the [(S,S) form] compound.

[0182] Separation conditions;

[0183] Column: CHIRALCEL OJ, 50Φ×500 mm, Daicel Chemical Industries, Ltd.

[0184] Eluant: hexane/ethanol=90/10

[0185] Flow rate: 25 ml per minute

[0186] The title [(S,S) form] compound:

[0187] Mp: 114-115° C. Mass spectrum (CI, m/z): 340 (M⁺+1) 1H-NMR spectrum (CDCl₃, δppm): 0.14 (dt; J=8 Hz, 5 Hz, 1H), 0.39 (dt; J=8 Hz, 5 Hz, 1H), 0.59-0.65 (m, 1H), 0.76-0.85 (m, 1H), 0.89 (d; J=6 Hz, 3H), 2.26 (s,3H), 2.36 (s, 3H), 4.13 (dd; J=15 Hz, 7 Hz, 1H), 4.27 (dd; J=15 Hz, 6Hz, 1H), 5.63(d; J=12 Hz, 1H), 5.68 (d; J=12.2 Hz, 1H), 7.05-7.12 (m, 2H), 7.47-7.52 (m, 2H ), 8.96(s, 1H). Optical rotation: [α]_(D) ²⁰=+19.0° (C=0.99, MeOH).

[0188] The antipode [(R,R) form] compound:

[0189] Mp: 114-115° C. Mass spectrum (CI, m/z): 340 (M⁺+1) NMR spectrum (CDCl₃, δppm): 0.15 (dt; J=8 Hz, 5 Hz, 1H), 0.39 (dt; J=8 Hz, 5 Hz, 1H), 0.58-0.66 (m, 1H), 0.78-0.85 (m, 1H), 0.89 (d; J=6 Hz, 3H), 2.26 (s, 3H), 2.37(s, 3H), 4.13 (dd; J=15 Hz, 7 Hz, 1H), 4.27 (dd; J=15 Hz, 6 Hz, 1H), 5.63 (d; J=12 Hz, 1H), 5.68 (d; J=12 Hz, 1H), 7.06-7.11 (m, 2H), 7.49-7.52 (m, 2H), 8.97 (s, 1H). Optical rotations: [α]_(D) ²⁰=18.8° (C=0.98, MeOH).

Test Example 1 Test on Activity of Proton•potassium-adenosine Triphosphatase (H⁺.K⁺-ATPase)

[0190] A microsomal fraction prepared in accordance with the method of Sachs, et al. [J. Bio. Chem., 251, 7690(1976)] by homogenizing a fresh gastric mucosal layer of swine and then subjecting the homogenate to density gradient ultra centrifugation was employed as a proton potassium-adenosine triphosphatase preparation. A solution (10 μl) of a test compound dissolved in dimethyl sulfoxide was added to 0.75 ml of a 70 mM tris hydrochloric acid buffer (5 mM magnesium chloride, 20 mM potassium chloride, pH=6.85) containing 30 to 80 μg/ml, in terms of the protein concentration, of the enzyme preparation. The mixture was incubated with 200 times/min of agitation at 37° C. for 45 minutes. The enzymatic reaction was started by adding 0.25 ml of an 8 mM solution of disodium adenosine triphosphate. After this enzymatic reaction was continued for 20 minutes, 1 ml of a 10% trichloroacetic acid—activated charcoal (100 mg) solution was added to terminate the reaction. The reaction mixture was centrifuged (at 4° C. and 3000 rpm for 15 minutes). Inorganic phosphoric acid formed by the hydrolysis of adenosine triphosphate in the supernatant was subjected to colorimetry by the method of Yoda, et al. [Biochem. Biophys. Res. Commun., 40, 880(1970)]. The amount of inorganic phosphoric acid in a reaction mixture free from potassium chloride was also measured. By subtracting this amount from the amount of inorganic phosphoric acid in the presence of potassium chloride, protonpotassium-adenosine triphosphatase activity (H⁺.K⁺-ATPase) was determined. An inhibition ratio (%) was determined from the active value of the control and the active value of the test compound at each concentration, whereby a 50% inhibitory concentration (IC₅₀ μg/ml) against protonpotassium-adenosine triphosphatase was determined. As a result, the compound of Example 2 had a 50% inhibitory concentration (IC₅₀) of 0.015 μg/ml, exhibiting excellent activity.

Test Example 2 Test for Inhibition on Gastric Acid Secretion in Rats

[0191] After a group of rats was fasted overnight, they were subjected to midline abdominal incision and their pylorus was ligated under anesthesia with ether. The stomach and duodenum were returned to their original positions in the body, followed by closing at the abdominal incision part. A test compound (0.3 to 10 mg/ml) was suspended in an aqueous solution containing 0.5% of sodium carboxymethylcellulose and 0.4% of Tween 80 (trade mark). The resulting suspension (1 ml/kg of body weight) was orally administered to the rats through a stomach tube. Four hours after the ligation, the rats were sacrificed by inhalation of CO₂ gas. They were subjected to abdominal incision to remove their stomach. The content of the stomach was collected in a glass-made graduated centrifuge tube. After centrifugation, the amount (ml) of the supernatant and the amount (ml) of the precipitate were measured. The precipitate of the amount exceeding 0.5 ml was regarded as feces and excluded from the data. The supernatant (100 μg) was poured into a test tube. Distilled water (4 ml) was added to the solution, and the solution was titrated to pH 7.0 with 0.01 N sodium hydroxide. A standard acid concentration solution obtained by adding 4 ml of distilled water to 100 μl of 0.1 N hydrochloric acid was titrated in a similar manner. Each parameter was calculated in accordance with the following equations:

[0192] (1) Acid concentration of gastric juice (mEq/l)=A/B×100

[0193] A: amount (ml) of sodium hydroxide required for titration of 100 μl of supernatant

[0194] B: amount (ml) of sodium hydroxide required for titration of 100 μl of 0.1 N hydrochloric acid

[0195] (2) Gastric acid output (AO, μEq/hr)=amount (ml) of supernatant of gastric juice×acid concentration of gastric juice (mEq/l)/4

[0196] (3) Inhibition ratio (%)=(C−D)/C×100

[0197] C: AO (μEq/hr) of vehicle-administered group

[0198] D: AO (μEq/hr) of test-compound-administered group

[0199] A 50% inhibitory dose (ID₅₀) was determined from a dose-inhibition ratio curve on which an inhibition ratio at each dose versus logarithmic dose was drawn in accordance with the least squares. 95% confidence limit was determined according to Fieller's equation. As the results, the compound of Example 2 exhibited excellent activity, that is, an ID₅₀ less than 10 mg/kg.

Test Example 3 Antibacterial Action Against Helicobacter Pylori

[0200] The antibacterial activity of the compound of the invention was evaluated by using Helicobacter pylori strains 9470, 9472 and 9474 and determining MIC (Minimum Inhibitory Concentration) of the compound of the invention against Helicobacter pylori.

[0201]Helicobacter pylori was cultured by plating for 4 days. A medium was prepared by dissolving Brain Heart Infusion Agar (product of Difco Laboratories) in a prescribed amount of distilled water, sterilizing in an autoclave, adding equine blood (product of Nippon Seibutsu Zairyo) to give a concentration thereof of 7% and then solidifying the mixture.

[0202] Under microaerophilic conditions, Helicobacter pylori which had been cultured at 37° C. for 4 days was suspended in physiological saline to give its viable count of about 10⁸ CFU/ml. The suspension was then diluted to 100 times and a portion (about 10 μl) of the diluted suspension was inoculated in a medium for measuring MIC. The medium employed for measuring MIC has the same composition as the preculture medium. A compound of this invention was dissolved in dimethyl sulfoxide (DMSO) and two-fold serial dilutions were made with sterilized water. After mixing the solution and the medium in a ratio of 1:99, a solidified product in the Petri dish was employed as an MIC measuring medium. In a similar manner to that employed for the preculture, Helicobacter pylori was cultured at 37° C. for 3 days under microaerophilic conditions. After completion of the culturing, growth of the bacteria in the inoculated portion was visually observed. The minimum concentration of a compound of this invention at which no bacterial growth was observed was designated as MIC (μg/ml). The compound of Example 2 exhibited excellent antibacterial activity, that is, an MIC less than 12.5 μg/ml. Formulation Example 1 Tablets The compound of Example 2  30.0 mg Lactose 144.0 mg Cornstarch  25.0 mg Magnesium stearate  1.0 mg 200.0 mg

[0203] A tablet is prepared using the ingredients above. The components are blended and compressed by a tablet machine to form a tablet weighing 200 mg. The tablet may be coated if necessary, for example, to form a sugar-coated tablet.

[0204] The compounds of formula (I) or pharmaceutically acceptable salts thereof of this invention exhibit potent gastric acid secretion inhibition activity, gastric mucous membrane protection activity and potent antibacterial activity against Helicobacter pylori and they have excellent properties as medicaments. The compounds of formula (I) or pharmaceutically acceptable salts thereof are useful as a medicament, particularly for prevention or for therapeutic treatment for ulcerative diseases such as peptic ulcer, acute or chronic gastric ulcer, gastrisis, reflux esophagitis, gastroesophageal reflux disorder, dyspepsia, gastric hyperacidity or Zollinger-Ellison syndrome etc. and for administration for prevention or for treatment of bacterial infections arising from Helicobacter pylori. 

1. A pyrrolopyridazine compound having the following formula or a pharmaceutically acceptable salt thereof:

wherein: R¹ is selected from the group consisting of C₂-C₆ alkenyl groups, halogeno C₂-C₆ alkenyl groups, C₃-C₇ cycloalkyl groups which may be optionally substituted with a C₁-C₆ alkyl group and C₃-C₇ cycloalkyl-C₁-C₆ alkyl groups which may be optionally substituted with a C₁-C₆ alkyl group; R² represents a C₁-C₆ alkyl group; R³ is selected from the group consisting of hydroxymethyl groups, C₂-C₆ aliphatic acyloxymethyl groups, C₆-C₁₀ arylcarbonyloxymethyl groups which may be optionally substituted with substituents selected from the group consisting of C₁-C₆ alkyl groups, C₁-C₆ alkoxy groups and halogen atoms, C₁-C₆ alkoxycarbonyloxymethyl groups, formyl groups, carboxyl groups, C₁-C₆ alkoxycarbonyl groups and C₆-C₁₀ aryloxycarbonyl groups which may be optionally substituted with substituents selected from the group consisting of C₁-C₆ alkyl groups, C₁-C₆ alkoxy groups and halogen atoms; R⁴ represents a C₆-C₁₀ aryl group which may be optionally substituted with substituents selected from the group consisting of C₁-C₆ alkyl groups, halogeno C₁-C₆ alkyl groups, C₁-C₆ alkoxy groups, halogeno C₁-C₆ alkoxy groups and halogen atoms; and A is selected from the group consisting of imino groups, oxygen atoms and sulfur atoms.
 2. A pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R¹ is selected from the group consisting of C₂-C₄ alkenyl groups, C₃-C₄ alkenyl groups substituted with fluoro or chloro, C₃-C₆ cycloalkyl groups which may be optionally substituted with a C₁-C₂ alkyl group and C₃-C₆ cycloalkyl-C₁-C₂ alkyl groups which may be optionally substituted with a C₁-C₂ alkyl group.
 3. A pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R¹ is selected from the group consisting of C₃-C₄ alkenyl groups, 3-chloro-2-propenyl groups, 3,3-difluoro-2-propenyl groups, 3,3-dichloro-2-propenyl groups, cyclopropyl groups, 2-methylcyclopropyl groups, 2-ethylcyclopropyl groups, cyclobutyl groups, cyclopentyl groups, 2-methylcyclopentyl groups, cyclohexyl groups, 2-methylcyclohexyl groups, cyclopropylmethyl groups, 2-methylcyclopropylmethyl groups, 2-ethylcyclopropylmethyl groups, cyclobutylmethyl groups, 2-methylcyclobutylmethyl groups, cyclopentylmethyl groups and 2-methylcyclohexylmethyl groups.
 4. A pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R¹ is selected from the group consisting of 2-propenyl groups, 2-butenyl groups, cyclopropyl groups, 2-methylcyclopropyl groups, cyclopentyl groups, 2-methylcyclopentyl groups, cyclohexyl groups, 2-methylcyclohexyl groups, cyclopropylmethyl groups, 2-methylcyclopropylmethyl groups, cyclopentylmethyl groups and 2-methylcyclohexylmethyl groups.
 5. A pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R¹ is selected from the group consisting of 2-propenyl groups, 2-butenyl groups, cyclopropyl groups, 2-methylcyclopropyl groups, cyclopropylmethyl groups and 2-methylcyclopropylmethyl groups.
 6. A pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R¹ is selected from the group consisting of 2-butenyl groups, cyclopropylmethyl groups and 2-methylcyclopropylmethyl groups.
 7. A pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R² is a C₁-C₄ alkyl group.
 8. A pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R² is a C₁-C₂ alkyl group.
 9. A pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R² is a methyl group.
 10. A pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R³ is selected from the group consisting of hydroxymethyl groups, C₂-C₆ aliphatic acyloxymethyl groups, benzoyloxymethyl groups which may be optionally substituted with a substituent selected from the group consisting of methyl groups, methoxy groups, fluoro and chloro, C₁-C₄ alkoxycarbonyloxymethyl groups, formyl groups, carboxyl groups, C₁-C₄ alkoxycarbonyl groups and phenyloxycarbonyl groups which may be optionally substituted with a substituent selected from the group consisting of methyl groups, methoxy groups, fluoro and chloro.
 11. A pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R³ is selected from the group consisting of hydroxymethyl groups, C₂-C₆ aliphatic acyloxymethyl groups, benzoyloxymethyl groups, C₁-C₂ alkoxycarbonyloxymethyl groups, formyl groups, carboxyl groups, C₁-C₂ alkoxycarbonyl groups and phenyloxycarbonyl groups.
 12. A pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R³ is selected from the group consisting of hydroxymethyl groups, C₂-C₄ aliphatic acyloxymethyl groups, C₁-C₂ alkoxycarbonyloxymethyl groups, formyl groups, carboxyl groups and C₁-C₂ alkoxycarbonyl groups.
 13. A pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R³ is selected from the group consisting of hydroxymethyl groups, C₂-C₃ aliphatic acyloxymethyl groups, formyl groups and carboxyl groups.
 14. A pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R³ is a hydroxymethyl group or an acetoxymethyl group.
 15. A pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R⁴ is a phenyl group which is substituted with 1 to 3 substituents selected from the group consisting of C₁-C₄ alkyl groups, halogeno C₁-C₄ alkyl groups, C₁-C₄ alkoxy groups, halogeno C₁-C₄ alkoxy groups, fluoro, chloro and bromo.
 16. A pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R⁴ is a phenyl group which is substituted with 1 to 3 substituents selected from the group consisting of a methyl group, a trifluoromethyl group, a methoxy group, a trifluoromethoxy groups, a difluoromethoxy group, fluoro, chloro and bromo.
 17. A pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R⁴ is a phenyl group which is substituted at the position(s) selected from the group consisting of 2-, 4- and 6-position of the phenyl group with 1 or 2 substituents selected from the group consisting of fluoro and chloro.
 18. A pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R⁴ is a phenyl group which is substituted at the 4-position, 2,4-positions or 2,6-positions of the phenyl group with 1 or 2 substituents selected from the group consisting of fluoro and chloro.
 19. A pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein A is an oxygen atom or a sulfur atom.
 20. A pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein A is an oxygen atom.
 21. A pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R¹ is selected from the group consisting of C₂-C₄ alkenyl groups, C₃-C₄ alkenyl groups substituted with fluoro or chloro, C₃-C₆ cycloalkyl groups which may be optionally substituted with a C₁-C₂ alkyl group and C₃-C₆ cycloalkyl-C₁-C₂ alkyl groups which may be optionally substituted with a C₁-C₂ alkyl group; R² is a C₁-C₄ alkyl group; R³ is selected from the group consisting of hydroxymethyl groups, C₂-C₆ aliphatic acyloxymethyl groups, benzoyloxymethyl groups which may be optionally substituted with a substituent selected from the group consisting of methyl groups, methoxy groups, fluoro and chloro, C₁-C₄ alkoxycarbonyloxymethyl groups, formyl groups, carboxyl groups, C₁-C₄ alkoxycarbonyl groups and phenyloxycarbonyl groups which may be optionally substituted with a substituent selected from the group consisting of methyl groups, methoxy groups, fluoro and chloro; R⁴ is a phenyl group which is substituted with 1 to 3 substituents selected from the group consisting of C₁-C₄ alkyl, halogeno C₁-C₄ alkyl, C₁-C₄ alkoxy, halogeno-C₁-C₄ alkoxy, fluoro, chloro and bromo; and A is an oxygen atom or a sufur atom.
 22. A pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R¹ is selected from the group consisting of C₃-C₄ alkenyl groups, 3-chloro-2-propenyl groups, 3,3-difluoro-2-propenyl groups, 3,3-dichloro-2-propenyl groups, cyclopropyl groups, 2-methylcyclpropyl groups, 2-ethylcyclopropyl groups, cyclobutyl groups, cyclopentyl groups, 2-methylcyclopentyl groups, cyclohexyl groups, 2-methylcyclohexyl groups, cyclopropylmethyl groups, 2-methylcyclopropylmethyl groups, 2-ethylcyclopropylmethyl groups, cyclobutylmethyl groups, 2-methylcyclobutylmethyl groups, cyclopentylmethyl groups and 2-methylcyclohexylmethyl groups; R² is a C₁-C₄ alkyl group; R³ is selected from the group consisting of hydroxymethyl groups, C₂-C₆ aliphatic acyloxymethyl groups, benzoyloxymethyl groups, C₁-C₂ alkoxycarbonyloxymethyl groups, formyl groups, carboxyl groups, C₁-C₂ alkoxycarbonyl groups and phenyloxycarbonyl groups; R⁴ is a phenyl group which is substituted with 1 to 3 substituents selected from the group consisting of methyl groups, trifluoromethyl groups, methoxy groups, trifluoromethoxy groups, difluoromethoxy groups, fluoro, chloro and bromo; and A is an oxygen atom or a sulfur atom.
 23. A pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R¹ is selected from the group consisting of 2-propenyl groups, 2-butenyl groups, cyclopropyl groups, 2-methylcyclopropyl groups, cyclopentyl groups, 2-methylcyclopentyl groups, cyclohexyl groups, 2-methylcyclohexyl groups, cyclopropylmethyl groups, 2-methylcyclopropylmethyl groups, cyclopentylmethyl groups and 2-methylcyclohexylmethyl groups; R² is a C₁-C₂ alkyl group; R³ is selected from the group consisting of hydroxymethyl groups, C₂-C₄ aliphatic acyloxymethyl groups, C₁-C₂ alkoxycarbonyloxymethyl groups, formyl groups, carboxyl groups and C₁-C₂ alkoxycarbonyl groups; R⁴ is a phenyl group which is substituted at the position(s) selected from the group consisting of 2-, 4- and 6-position of the phenyl group with 1 or 2 substituents selected from the group consisting of fluoro and chloro; and A is an oxygen atom.
 24. A pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R¹ is selected from the group consisting of 2-propenyl groups, 2-butenyl groups, cyclopropyl groups, 2-methylcyclopropyl groups, cyclopropylmethyl groups and 2-methylcyclopropylmethyl groups, R² is a C₁-C₂ alkyl group; R³ is selected from the group consisting of hydroxymethyl groups, C₂-C₃ aliphatic acyloxymethyl groups, formyl groups and carboxyl groups; R⁴ is a phenyl group which is substituted at the position(s) selected from the group consisting of 2-, 4- and 6-position of the phenyl group with 1 or 2 substituents selected from the group consisting of fluoro and chloro; and A is an oxygen atom.
 25. A pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R¹ is selected from the group consisting of 2-butenyl groups, cyclopropylmethyl groups and 2-methylcyclopropylmethyl groups; R² is a methyl group; R³ is a hydroxymethyl group or an acetoxymethyl group; R⁴ is a phenyl group which is substituted at the 4-position, 2,4-positions or, 2,6-positions of the phenyl group with 1 or 2 substituents selected from the group consisting of fluoro and chloro; and A is an oxygen atom.
 26. A pyrrolopyridazine compound selected from the following group or a pharmaceutically acceptable salt thereof: 1-(2-butenyl)-7-(4-fluorobenzyloxy)-3-hydroxymethyl-2-methylpyrrolo[2,3-d]pyridazine, 7-(4-fluorobenzyloxy)-3-hydroxymethyl-2-methyl-1-(2-methylcyclopropylmethyl)pyrrolo[2,3-d]pyridazine, 1-(2-butenyl)-7-(2,4-difluorobenzyloxy)-3-hydroxymethyl-2-methylpyrrolo[2,3-d]pyridazine, 7-(2,4-difluorobenzyloxy)-3-hydroxymethyl-2-methyl-1-(2-methylcyclopropylmethyl)pyrrolo[2,3-d]pyridazine, 3-acetoxymethyl-7-(4-fluorobenzyloxy)-2-methyl-1-(2-methylcyclopropylmethyl)pyrrolo[2,3-d]pyridazine, and 3-acetoxymethyl-7-(2,4-difluorobenzyloxy)-2-methyl-1-(2-methylcyclopropylmethyl)pyrrolo[2,3-d]pyridazine.
 27. A pyrrolopyridazine compound according to claim
 26. 28. A pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1, which is 3-acetoxymethyl-7-(4-fluorobenzyloxy)-2-methyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridazine or a pharmaceutically acceptable salt thereof.
 29. A pyrrolopyridazine compound according to claim
 28. 30. A pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1, which is 7-(4-fluorobenzyloxy)-3-hydroxymethyl-2-methyl-1-[(1S,2S) -2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridazine or a pharmaceutically acceptable salt thereof.
 31. A pyrrolopyridazine compound according to claim
 30. 32. A pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1, which is 7-(4-fluorobenzyloxy)-3-formyl-2-methyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridazine or a pharmaceutically acceptable salt thereof.
 33. A pyrrolopyridazine compound according to claim
 32. 34. A pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1, which is 3-carboxy-7-(4-fluorobenzyloxy)-2-methyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridazine or a pharmaceutically acceptable salt thereof.
 35. A pyrrolopyridazine compound according to claim
 34. 36. A pharmaceutical composition comprising (i) a pharmacologically acceptable carrier and (ii) a pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to
 35. 37. A method for the prophylaxis or treatment of an ulcerative disease which comprises administering to a warm-blooded animal in need thereof a pharmaceutically effective amount of a pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to anyone of claims 1 to
 35. 38. A method for the prophylaxis or treatment of an ulcerative disease which comprises administering to a human in need thereof a pharmaceutically effective amount of a pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to anyone of claims 1 to
 35. 39. A method for the treatment of a Helicobacter pylori infection in a warm-blooded animal which comprises administering to said warm-blooded animal a pharmaceutically effective amount of a pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to anyone of claims 1 to
 20. 40. A method for the treatment of a Helicobacter pylori infection in a human which comprises administering to said human a pharmaceutically effective amount of a pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to anyone of claims 21 to
 35. 